Heterocyclic degronimers for target protein degradation

ABSTRACT

This invention provides heterocyclic compounds that bind to E3 Ubiquitin Ligase (typically through cereblon) (“Degrons”), which can be used as is or linked to a Targeting Ligand for a selected Target Protein for therapeutic purposes and methods of use and compositions thereof as well as methods for their preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/872,225, filed on May 11, 2020, which is a divisional of U.S. patentapplication Ser. No. 16/186,339, filed on Nov. 9, 2018, which is acontinuation of International Application No. PCT/US2017/032051, filedin the International Patent Cooperation Treaty, U.S. Receiving Office onMay 10, 2017, which claims the benefit of priority to U.S. ApplicationNo. 62/334,395, filed May 10, 2016. The entirety of these applicationsare hereby incorporated by reference herein for all purposes

FIELD OF THE INVENTION

This invention provides heterocyclic compounds that bind to E3 UbiquitinLigase (typically through cereblon) (“Degrons”), which can be used as isor linked to a Targeting Ligand for a selected Target Protein fortherapeutic purposes and methods of use and compositions thereof as wellas methods for their preparation.

BACKGROUND

Protein degradation is a highly regulated and essential process thatmaintains cellular homeostasis. The selective identification and removalof damaged, misfolded, or excess proteins is achieved via theubiquitin-proteasome pathway (UPP). The UPP in fact is central to theregulation of almost all cellular processes, including antigenprocessing, apoptosis, biogenesis of organelles, cell cycling, DNAtranscription and repair, differentiation and development, immuneresponse and inflammation, neural and muscular degeneration,morphogenesis of neural networks, modulation of cell surface receptors,ion channels and the secretory pathway, the response to stress andextracellular modulators, ribosome biogenesis and viral infection.

Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitinligase to a terminal lysine residue marks the protein for proteasomedegradation, where the protein is digested into small peptides andeventually into its constituent amino acids that serve as buildingblocks for new proteins. Defective proteasomal degradation has beenlinked to a variety of clinical disorders including Alzheimer's disease,Parkinson's disease, Huntington's disease, muscular dystrophies,cardiovascular disease, and cancer among others.

There are over 600 E3 ubiquitin ligases which facilitate theubiquitination of different proteins in vivo, which can be divided intofour families: HECT-domain E3s, U-box E3s, monomeric RING E3s andmulti-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487)titled “Genome-wide and functional annotation of human E3 ubiquitinligases identifies MULAN, a mitochondrial E3 that regulates theorganelle's dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol.Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligasemechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434)titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem.2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures,new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014,14, 233-347) titled “Roles of F-box proteins in cancer.”.

In 1995, Gosink et al. (Proc. Natl. Acad. Sci. USA 1995, 92, 9117-9121)in a publication titled “Redirecting the Specificity of Ubiquitinationby Modifying Ubiquitin-Conjugating Enzymes”, provided proof of conceptin vitro that engineered peptides can selectively direct ubiquitinationof intracellular proteins. The publication by Nawaz et al. (Proc. Natl.Acad. Sci. U.S.A. 1999, 96, 1858-1862) titled “Proteasome-DependentDegradation of the Human Estrogen Receptor” describes ER degradationwhich takes advantage of the ubiquitin-proteasome pathway.

Proteinex, Inc. filed a patent application in February 1999 that issuedas U.S. Pat. No. 6,306,663 claiming a method of generating a compoundfor activating the ubiquitination of a Target Protein which comprisescovalently linking a Target Protein binding element able to bindspecifically to the Target Protein via a ubiquitination recognitionelement. Proteinex described that the invention can be used to controlprotein levels in eukaryotes. While the '663 patent may have been basedon the first patent application to describe the high level concept ofhow to manipulate the UPP system to degrade selected proteins in vivo,the patent did not provide sufficient detail to allow persons of skillto easily construct the range of proposed compounds. For example, forthe ubiquitination recognition elements, the skilled person was toldamong other things to use standard methods for drug discovery and screenfor appropriate small molecules that would bind to the ligase. Proteinexalso emphasized the use of peptides as ubiquitination recognitionelements, which can pose significant difficulties for oral drugadministration.

Since then, harnessing the ubiquitin-proteasome pathway for therapeuticintervention has received significant interest from the scientificcommunity. The publication by Zhou et al. from Harvard Medical School(Mol. Cell 2000, 6, 751-756) titled “Harnessing the UbiquitinationMachinery to Target the Degradation of Specific Cellular Proteins”described an engineered receptor capable of directing ubiquitination inmammalian and yeast cells.

Following from these early publications and others in the mid to late1990s, it was also recognized by Craig Crews and coworkers (YaleUniversity) that a molecule that is capable of binding a Target Proteinand a ubiquitin ligase may cause the Target Protein to be degraded.Their first description of such compounds was provided in U.S. Pat. No.7,041,298 filed in September 2000 by Deshaies et al. and granted in May2006 titled “Proteolysis Targeting Chimeric Pharmaceutical”, whichdescribed a “PROTAC” consisting of a small molecule binder of MAP-AP-2linked to a peptide capable of binding the F-box protein f-TRCP.Information in the '298 patent is also presented in the correspondingpublication by Sakamoto et al. (Proc. Natl. Acad. Sci. USA 2001, 98,8554-8559) titled “Protacs: Chimeric Molecules That Target Proteins tothe Skp1-Cullin-F Box Complex for Ubiquitination and Degradation”. Thepublication by Sakamoto et al. (Mol. Cell. Proteomics 2003, 2,1350-1358) titled “Development of Protacs to Target Cancer-PromotingProteins for Ubiquitination and Degradation” describes an analogousPROTAC (PROTAC2) that instead of degrading MAP-AP-2 degrades estrogenand androgen receptors.

The first E3 ligase successfully targeted with a small molecule wasMDM2, which ubiquitinates the tumor suppressor p53. The targeting ligandwas an HDM2/MDM2 inhibitor identified in Vassilev et al. (Science 2004,303, 844-848) titled “In Vivo Activation of the P53 Pathway bySmall-Molecule Antagonists of MDM2”.

Other examples of direct small molecule-induced recruitment of TargetProteins to the proteasome for degradation on addition to cultured cellswere described in 2004 (Schneekloth et al. (J. Am. Chem. Soc. 2004, 126,3748-3754) titled “Chemical Genetic Control of Protein Levels: Selectivein Vivo Targeted Degradation”). Schneekloth et al. describe adegradation agent (PROTAC3) that targets the FK506 binding protein(FKBP12) and shows that both PROTAC2 and PROTAC3 hit their respectivetargets with green fluorescent protein (GFP) imaging. The publication bySchneekloth et al. (ChemBioChem 2005, 6, 40-46) titled “ChemicalApproaches to Controlling Intracellular Protein Degradation” describedthe state of the field at the time.

The publication by Schneekloth et al. (Bioorg. Med. Chem. Lett. 2008,18, 5904-5908) titled “Targeted Intracellular Protein DegradationInduced by a Small Molecule: En Route to Chemical Proteomics” describesa degradation agent that consists of two small molecules linked by PEGthat in vivo degrades the androgen receptor by concurrently binding theandrogen receptor and ubiquitin E3 ligase.

WO 2013/170147 filed by Crews et al. titled “Compounds Useful forPromoting Protein Degradation and Methods of Using Same” describescompounds comprising a protein degradation moiety covalently bound to alinker, wherein the C log P of the compound is equal to or higher than1.5. In particular, the specification discloses protein degradingcompounds that incorporate certain small molecules that can bind to anE3 ubiquitin ligase.

In unrelated parallel research, scientists were investigatingthalidomide toxicity. Ito et al. (Science 2010, 327, 1345-1350) titled“Identification of a Primary Target of Thalidomide Teratogenicity”,described that cereblon is a thalidomide binding protein. Cereblon formspart of an E3 ubiquitin ligase protein complex which interacts withdamaged DNA binding protein 1, forming an E3 ubiquitin ligase complexwith Cullin 4 and the E2-binding protein ROC1 (also known as RBX1) whereit functions as a substrate receptor to select proteins forubiquitination. The study revealed that thalidomide-cereblon binding invivo may be responsible for thalidomide teratogenicity. After thediscovery that thalidomide causes teratogenicity in the mid-1960's, thecompound and related structures were notwithstanding found to be usefulas anti-inflammatory, anti-angiogenic and anti-cancer agents (seeBartlett et al. (Nat. Rev. Cancer 2004, 4, 314-322) titled “TheEvolution of Thalidomide and Its Imid Derivatives as AnticancerAgents”).

The disclosure that thalidomide binds to the cereblon E3 ubiquitinligase let to research to investigate incorporating thalidomide andcertain derivatives into compounds for the targeted destruction ofproteins. Two seminal papers were published in Science in 2014: G. Lu etal., The Myeloma Drug Lenalidomide Promotes the Cereblon-DependentDestruction of Ikaros Proteins, Science, 343, 305-309 (2014); and J.Kronke et al., Lenalidomide Causes Selective Degradation of IKZF1 andIKZF3 in Multiple Myeloma Cells, Science, 343, 301-305 (2014).

U.S. 2014/0356322 assigned to Yale University, GlaxoSmithKline, andCambridge Enterprise Limited University of Cambridge titled “Compoundsand Methods for the Enhanced Degradation of Target Proteins & OtherPolypeptides by an E3 Ubiquitin Ligase” describes protein degradingcompounds that bind to the VHL E3 Ubiquitin Ligase. See also Buckley etal. (J. Am. Chem. Soc. 2012, 134, 4465-4468) titled “Targeting the VonHippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt theVhl/Hif-1alpha Interaction”.

WO 2015/160845 assigned to Arvinas Inc. titled “Imide Based Modulatorsof Proteolysis and Associated Methods of Use” describes proteindegradation compounds that incorporate thalidomide and certainderivatives which bind to a cereblon E3 ligase.

Additional publications in this area include the following: Lu et al.(Chem. Biol. 2015, 22, 755-763) titled “Hijacking the E3 UbiquitinLigase Cereblon to Efficiently Target Brd4”; Bondeson et al. (Nat. Chem.Biol. 2015, 11, 611-617) titled “Catalytic in Vivo Protein Knockdown bySmall-Molecule Protacs”; Gustafson et al. (Angewandte Chemie,International Edition in English 2015, 54, 9659-9662) titled“Small-Molecule-Mediated Degradation of the Androgen Receptor throughHydrophobic Tagging”; Lai et al. (Angewandte Chemie, InternationalEdition in English 2016, 55, 807-810) titled “Modular Protac Design forthe Degradation of Oncogenic Bcr-Abl”; Toure et al. (Angew. Chem. Int.Ed. 2016, 55, 1966-1973) titled “Small-Molecule Protacs: New Approachesto Protein Degradation”; and Winter et al. (Science 2015, 348,1376-1381) titled “Drug Development. Phthalimide Conjugation as aStrategy for in Vivo Target Protein Degradation” describes thalidomidebased Target Protein degradation technology.

U.S. 2016/0058872 assigned to Arvinas Inc. titled “Imide BasedModulators of Proteolysis and Associated Methods of Use” and U.S.2016/0045607 assigned to Arvinas Inc. titled “Estrogen-related ReceptorAlpha Based PROTAC Compounds and Associated Methods of Use” describecertain estrogen receptor degrading compounds.

While progress has been made in the area of modulation of the UPP for invivo protein degradation, it would be useful to have additionalcompounds and approaches to more fully harness the UPP for therapeutictreatments.

It is an object of the present invention to provide new compounds,methods, compositions, and methods of manufacture that are useful todegrade selected proteins in vivo.

SUMMARY

Heterocyclic compounds that bind to E3 Ubiquitin Ligase (typicallythrough cereblon) (“Degrons”) are provided, which can be used as is orlinked to a Targeting Ligand for a selected Target Protein fortherapeutic purposes and methods of use and compositions thereof as wellas methods for their preparation and manufacture. A Degron as describedherein when covalently linked (Linker) to a ligand (Targeting Ligand)for a Target Protein is referred to as a “Degronimer” because theyaccomplish degradation of the Target Protein by the proteasome. TheDegronimer includes a “Targeting Ligand” that binds (typicallynon-covalently) to a selected Target Protein, a “Degron” which binds(typically non-covalently) to an E3 Ligase and optionally a linker thatcovalently links the Targeting Ligand to the Degron.

A Degronimer provided herein or its pharmaceutically acceptable salt orcomposition can be used to treat a disorder which is mediated by theTarget Protein bound to the Targeting Ligand.

In one embodiment, the selected Target Protein is derived from a genethat has undergone an amplification, translocation, deletion, orinversion event which causes or is caused by a medical disorder. Incertain aspects, the selected Target Protein has beenpost-translationally modified by one, or combinations, ofphosphorylation, acetylation, acylation including propionylation andcrotylation, N-linked glycosylation, amidation, hydroxylation,methylation, poly-methylation, O-linked glycosylation,pyrogultamoylation, myristoylation, farnesylation, geranylgeranylation,ubiquitination, sumoylation, or sulfation which causes or is caused by amedical disorder. In an alternative embodiment, the Target Protein iscovalently modified by a Targeting Ligand that has been functionalizedto produce a degrader, and the covalent ligand can be irreversible orreversible.

In one aspects a compound of Formula I or Formula II is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative orprodrug, optionally in a pharmaceutically acceptable carrier, to form apharmaceutically acceptable composition; wherein:

A is CR⁸R⁹, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

A′ is CR¹R², C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

A″ is CR³R⁴, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

X is independently NH, NR¹¹, CH₂, CHR¹², C(R¹²)₂, O, or S;

Z is O, S, CH₂, CH(C₁-C₄alkyl), and C(C₁-C₄alkyl)₂;

n is 0, 1, 2, or 3;

is a single or double bond;

R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, and R¹³ are independently selected fromhydrogen, alkyl, hydroxyl, alkoxy, amine, —NH(aliphatic, includingalkyl), —Nalkyl₂;

or R¹ and R² form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-,5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O;

or R³ and R⁴ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-,5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O;

or R⁶ and R⁷ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-,5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O;

or R⁸ and R⁹ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-,5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O;

or R¹ and R³ form a 1, 2, 3 or 4 carbon bridged ring;

or R¹ and R⁷ form a 1, 2, 3 or 4 carbon bridged ring;

or R³ and R⁷ form a 1, 2, 3 or 4 carbon bridged ring;

or R¹³ and R¹ form a 3, 4, 5, or 6 carbon fused ring;

or R¹³ and R⁶ form a 3, 4, 5, or 6 carbon fused ring;

or R¹³ and R⁴ form a 1, 2, 3 or 4 carbon bridged ring;

or R¹³ and R⁵ form a 3, 4, 5, or 6 carbon fused ring wherein R⁵ is onthe carbon alpha to R¹³ or a 1, 2, 3, or 4 carbon bridged ring whereinR⁵ is not on the carbon alpha to R¹³;

in a typical embodiment W¹ is C═O;

in another typical embodiment W² is C═O;

in another typical embodiment both W¹ and W² are C═O and X is NH;

R⁵ is selected at each instance from: alkyl, alkene, alkyne, halogen,hydroxyl, alkoxy, azide, amino, —NH(aliphatic, including alkyl),—N(aliphatic, including alkyl)₂, —NHSO₂ (aliphatic, including alkyl),—N(alkyl)SO₂ (aliphatic, including alkyl), —NHSO₂ (aryl includingheteroaryl), —N(aliphatic, including alkyl)SO₂aryl, —NHSO₂alkenyl,—N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, aliphatic,heteroaliphatic, aryl, heteroaryl, heterocyclic, and haloalkyl;

or two R⁵ substituents together with the carbon atom(s) to which theyare bound can form a 3, 4, 5 or 6 membered ring;

R¹⁰ is Linker-Targeting Ligand;

Q¹, Q², Q³, and Q⁴ are independently selected from CH, CR¹², N andwherein in certain embodiments the number of nitrogen atoms is 0, 1, 2,or 3 per ring (as allowed by context) and is selected to produce astable ring and a pharmaceutically acceptable Degronimer. When the Q isin a six-membered ring (unfused or fused), and atleast one Q isnitrogen, the ring can be, in non-limiting embodiments as allowed bycontext, a pyridine, diazine, triazine, pyrimidine, pyridazine,pyrazine, triazine or tetrazine.

R¹¹ is independently selected from alkyl, alkenyl, alkynyl, C(O)H,—C(O)OH, —C(O)alkyl, —C(O)Oalkyl, aliphatic, heteroaliphatic, aryl,heteroaryl or heterocyclic;

R¹² is independently selected from alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic,including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic,including alkyl), —N(aliphatic, including alkyl)₂, —NHSO₂ (aliphatic,including alkyl), —N(aliphatic, including alkyl)SO₂ (aliphatic includingalkyl, —NHSO₂ (aryl, including hetereoaryl), —N(aliphatic, includingalkyl)SO₂aryl, —NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl,—N(alkyl)SO₂alkynyl, cyano, nitro, nitroso, —SH, —Salkyl, and haloalkyl,aliphatic, heteroaliphatic, aryl, heteroaryl and heterocyclic;

Linker is a chemical group that attaches the Degron to a TargetingLigand;

Targeting Ligand is a moiety that is capable of binding to or binds to aTarget Protein, and wherein the Target Protein is a mediator of diseasein a host, as further defined herein;

wherein in certain embodiments the compound satisfies at least one of a,b, c, d, e, f, g, h, i, j, k, l, or m:

-   -   a. n is 1 or 2;    -   b. at least one of R¹, R², R³, or R⁴ is alkyl;    -   c. R¹ and R² form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   d. R³ and R⁴ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   e. R⁶ and R⁷ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   f. R⁸ and R⁹ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   g. R¹ and R³ form a 1 or 2 carbon bridged ring;    -   h. R¹ and R¹³ form a 3, 4, 5, or 6 carbon fused ring;    -   i. R⁴ and R¹³ form a 1 or 2 carbon bridged ring;    -   j. A is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂;    -   k. A′ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂    -   l. A″ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂; or    -   m. X is O, or S.

In one embodiment, the compound of Formula I is selected from:

In another aspect of the present invention a compound of Formula III isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof; wherein m is 1 or 3,and the other variables are as described above.

Linker is a chemical group that attaches the Degron to a TargetingLigand.

Targeting Ligand is a moiety that is capable of binding to or binds to aTarget Protein, and wherein the Target Protein is a mediator of diseasein a host, as defined in detail below.

Formula I, Formula II, and Formula III are bifunctional compounds withheterocyclic E3 Ubiquitin Ligase targeting moieties (Degrons) linked viaa Linker to a Targeting Ligand (described in more detail below), whichfunction to recruit Target Protein to E3 Ubiquitin Ligase fordegradation. In certain embodiments, the disorder is selected from abenign growth, neoplasm, tumor, cancer, immune disorder, autoimmunedisorder, inflammatory disorder, graft-versus-host rejection, infection,including a viral infection, bacterial infection, an amyloid-basedproteinopathy, a proteinopathy, or a fibrotic disorder. In a typicalembodiment, the patient is a human. One non-limiting example of adisorder treatable by such compounds is abnormal cellular proliferation,such as a tumor or cancer, wherein the Target Protein is an oncogenicprotein or a signaling mediator of an abnormal cellular proliferativepathway and its degradation decreases abnormal cell growth.

In one embodiment, the present invention provides heterocyclic moietieswhich are covalently linked to a Target Protein ligand through a Linkerwhich can be of varying length and functionality. In one embodiment, theheterocyclic Degron moiety is linked directly to the Targeting Ligand(i.e., the Linker is a bond). In certain embodiments, the Linker can beany chemically stable group that attaches the heterocyclic Degron to theTargeting Ligand. In a typical embodiment, the Linker has a chain of 2to 14, 15, 16, 17, 18 or 20 or more carbon atoms of which one or morecarbons can be replaced by a heteroatom such as O, N, S, P, as long asthe resulting molecule has a stable shelf life for at least 2 months, 3months, 6 months or 1 year as part of a pharmaceutically acceptabledosage form, and itself is pharmaceutically acceptable. In certainembodiments the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14contiguous atoms in the chain. For example, the chain may include 1 ormore ethylene glycol units, and in some embodiments, may have at least2, 3, 4, 5, 6, 7, 8, 9, or 10 or more contiguous, partially contiguousor non-contiguous ethylene glycol units in the Linker. In certainembodiments the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 brancheswhich can be independently alkyl, heteroalkyl, aryl, heteroaryl,alkenyl, or alkynyl substituents, which in one embodiment, each branchhas 10, 8, 6, 4, 3, 2 carbons or one carbon.

In one embodiment, the Target Protein is a protein that is not druggablein the classic sense in that it does not have a binding pocket or anactive site that can be inhibited or otherwise bound, and cannot beeasily allosterically controlled. In another embodiment, the TargetProtein is a protein that is druggable in the classic sense. Examples ofTarget Proteins are provided below.

In an alternative embodiment, a heterocyclic Degron of Formula III, IV,or VI as described herein can be used alone (i.e., not as part of aDegronimer) as an in vivo binder of cereblon, which can be administeredto a host, for example, a human, in need thereof, in an effectiveamount, optionally as a pharmaceutically acceptable salt, and optionallyin a pharmaceutically acceptable composition, for any therapeuticindication which can be treated by modulating the function and oractivity of the cereblon-containing E3 Ubiquitin Ligase Protein Complex,including but not limited to uses known for the cereblon bindersthalidomide, pomalidomide or lenalidomide. In certain alternativeembodiments, the compound of Formula III, IV or VI can activate,decrease or change the natural activity of cereblon.

Thus, in another aspect of the present invention a compound of FormulaIV or Formula V is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative,prodrug, and/or a pharmaceutically acceptable composition thereof;wherein:

wherein the variables are as described above and in certain embodimentsat least one of: a, b, c, d, e, f, g, h, i, or j is required:

-   -   a. R¹ and R² form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   b. R³ and R⁴ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   c. R⁶ and R⁷ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   d. R⁸ and R⁹ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   e. R¹ and R³ form a 1 or 2 carbon bridged ring;    -   f. R¹ and R¹³ form a 3, 4, 5, or 6 membered fused ring;    -   g. R⁴ and R¹³ form a 1 or 2 carbon bridged ring;    -   h. A is P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl,        P(O)OH, or P(O)NH₂;    -   i. A′ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂; or    -   j. A″ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂.

In one embodiment, the compound of Formula III is selected from:

In another aspect of the present invention a compound of Formula VI isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or aprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition;

wherein the variables are as described above and in certain embodimentsat least one of: a, b, c, d, e, f, g, h, i, j, k, l, or m is required:

-   -   a. m is 3 and n is not 0;    -   b. R¹ and R² form a spirocycle;    -   c. R³ and R⁴ form a spirocycle;    -   d. R⁶ and R⁷ form a spirocycle;    -   e. R⁸ and R⁹ form a spirocycle;    -   f. R¹ and R³ form a 1 or 2 carbon bridged ring;    -   g. R¹ and R¹³ form a 3, 4, 5, or 6 carbon fused ring;    -   h. R⁴ and R¹³ form a 1 or 2 carbon bridged ring;    -   i. R¹³ and R⁵ form a 3, 4, 5, or 6 carbon fused ring;    -   j. R¹³ and R⁵ form a 1 or 2 carbon bridged ring;    -   k. A is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂;    -   l. A′ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂; or    -   m. A″ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂;

The compounds of Formula IV, Formula V and Formula VI do not include aLinker or a Targeting Ligand. These Formula IV, Formula V and Formula VIcompounds for example, are useful as therapeutic agents for any disorderthat can be treated by binding to the cereblon subunit of the E3 Ligase,when administered in an effective amount to a host, including a human,for the treatment of a medical disorder. Disorders include, but are notlimited to, abnormal cellular proliferation, including a tumor orcancer, or a myelo- or lymphoproliferative disorder such as B- or T-celllymphomas, multiple myeloma, Waldenstrom's macroglobulinemia,Wiskott-Aldrich syndrome, or a post-transplant lymphoproliferativedisorder; an immune disorder, including autoimmune disorders such asAddison disease, Celiac disease, dermatomyositis, Graves disease,thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis,lupus, or type I diabetes; a disease of cardiac malfunction, includinghypercholesterolemia; an infectious disease, including viral and/orbacterial infections; an inflammatory condition, including asthma,chronic peptic ulcers, tuberculosis, rheumatoid arthritis,periodontitis, ulcerative colitis, Crohn's disease, or hepatitis.

In certain embodiments, the compound of Formula I, Formula II, FormulaIII, Formula IV, Formula V, or Formula VI has at least one desiredisotopic substitution of an atom, at an amount above the naturalabundance of the isotope, i.e., enriched. In one embodiment, thecompound of Formula I, Formula II, Formula III, Formula IV, Formula V,or Formula VI includes a deuterium or multiple deuterium atoms.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, suitable methods and materials are described below.All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed application. Inthe case of conflict, the present specification, including definitions,will control. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting.

Other features and advantages of the present invention will be apparentfrom the following detailed description and claims.

The present invention thus includes at least the following features:

(a) a heterocyclic compound of Formula I, Formula II, Formula III,Formula IV, Formula V, or Formula VI as described herein, andpharmaceutically acceptable salts, isotopic derivative (including adeuterated derivative) and prodrugs thereof;

(b) a heterocyclic compound of Formula I, Formula II or Formula III, forthe treatment of a disorder that is mediated by a selected TargetProtein, wherein the compound includes a Targeting Ligand for the TargetProtein, and wherein the heterocyclic compound is optionally linked tothe Targeting Ligand through a Linker;

(c) use of a compound of Formula I, Formula II, or Formula III in aneffective amount in the treatment of a patient, including a human, witha disorder mediated by a Target Protein, including abnormal cellularproliferation such as a tumor or cancer, an autoimmune disorder orinflammatory disorder, a cardiac disorder, an infectious disease, orother disorder that responds to such treatment;

(d) use of a compound of Formula IV, Formula V, or Formula VI in aneffective amount, in the treatment of a patient, including a human, withabnormal cellular proliferation such as a tumor or cancer, an autoimmunedisorder or inflammatory disorder, a cardiac disorder, an infectiousdisease, or other disorder that responds to such treatment;

(e) use of a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI, and pharmaceutically acceptable salts andprodrugs thereof in the manufacture of a medicament for the treatment ofa medical disorder;

(f) a method for manufacturing a medicament intended for the therapeuticuse of treating a disorder characterized in that a compound of FormulaI, Formula II, Formula III, Formula IV, Formula V, or Formula VI asdescribed herein is used in the manufacture;

(g) a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI as described herein, and pharmaceuticallyacceptable salts and prodrugs thereof that are useful in the treatmentof an abnormal cellular proliferation such as cancer, including any ofthe cancers described herein;

(h) use of a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI and pharmaceutically acceptable salts andprodrugs thereof in the manufacture of a medicament for the treatment ofan abnormal cellular proliferation such as cancer, including any of thecancers described herein;

(i) a method for manufacturing a medicament intended for the therapeutictreatment of an abnormal cellular proliferation such as cancer,including any of the cancers described herein, characterized in that acompound of Formula I, Formula II, Formula III, Formula IV, Formula V,or Formula VI as described herein is used in the manufacture;

(j) a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI as described herein, and pharmaceuticallyacceptable salts, isotopic derivatives and prodrugs thereof that areuseful in the treatment of a tumor, including any of the tumorsdescribed herein;

(k) use of a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI, and pharmaceutically acceptable salts andprodrugs thereof in the manufacture of a medicament for the treatment ofa tumor, including any of the tumors described herein;

(l) a method for manufacturing a medicament intended for the therapeutictreatment of a tumor, including any of the tumors described herein,characterized in that a compound of Formula I, Formula II, Formula III,Formula IV. Formula V, or Formula VI as described herein is used in themanufacture;

(m) a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI as described herein, and pharmaceuticallyacceptable salts and prodrugs thereof that are useful in the treatmentof an immune, autoimmune or inflammatory disorder;

(n) use of a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI and pharmaceutically acceptable salts andprodrugs thereof in the manufacture of a medicament for the treatment ofan immune, autoimmune or inflammatory disorder;

(o) a method for manufacturing a medicament intended for the therapeuticuse of treating an immune, autoimmune or inflammatory disorder,characterized in that a compound of Formula I, Formula II, Formula III,Formula IV. Formula V, or Formula VI as described herein is used in themanufacture;

(p) a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI as described herein, and pharmaceuticallyacceptable salts and prodrugs thereof that are useful in the treatmentof an infection, including a viral infection, including but not limitedto HIV, HBV, HCV and RSV;

(q) use of a compound of Formula I, Formula II, or Formula III, andpharmaceutically acceptable salts and prodrugs thereof in themanufacture of a medicament for the treatment of an infection, includinga viral infection, including but not limited to HIV, HBV, HCV and RSV;

(r) a method for manufacturing a medicament intended for the therapeutictreatment of an infection, including a viral infection including but notlimited to HIV, HBV, HCV and RSV, characterized in that a compound ofFormula I, Formula II, or Formula III as described herein is used in themanufacture;

(s) a pharmaceutical formulation comprising an effective host-treatingamount of the compound of Formula I, Formula II, Formula III, FormulaIV, Formula V, or Formula VI or a pharmaceutically acceptable salt orprodrug thereof together with a pharmaceutically acceptable carrier ordiluent;

(t) a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI as described herein as a mixture of enantiomersor diastereomers (as relevant), including as a racemate;

(u) a compound of Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI as described herein in enantiomerically ordiastereomerically (as relevant) enriched form, including as an isolatedenantiomer or diastereomer (i.e., greater than 85, 90, 95, 97 or 99%pure); and,

(v) a process for the preparation of therapeutic products that containan effective amount of a compound of Formula I, Formula II, Formula III,Formula IV, Formula V, or Formula VI, as described herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A-1C present examples of Retenoid X Receptor (RXR) TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1D-1F present examples of general Dihydrofolate reductase (DHFR)Targeting Ligands wherein R is the point at which the Linker isattached.

FIG. 1G presents examples of Bacillus anthracis Dihydrofolate reductase(BaDHFR) Targeting Ligands wherein R is the point at which the Linker isattached.

FIG. 1H-1J present examples of Heat Shock Protein 90 (HSP90) TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1K-1Q present examples of General Kinase and Phosphatase TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1R-1S present examples of Tyrosine Kinase Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 1T presents examples of Aurora Kinase Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1U presents examples of Protein Tyrosine Phosphatase TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1V presents examples of ALK Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1W presents examples of ABL Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1X presents examples of JAK2 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1Y-1Z present examples of MET Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1AA presents examples of mTORC1 and/or mTORC2 Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 1BB-1CC present examples of Mast/stem cell growth factor receptor(SCFR), also known as c-KIT receptor, Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1DD presents examples of IGF1R and/or IR Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 1EE-1FF present examples of HDM2 and/or MDM2 Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 1GG-1MM present examples of BET Bromodomain-Containing ProteinTargeting Ligands wherein R is the point at which the Linker isattached.

FIG. 1NN presents examples of HDAC Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1OO presents examples of RAF Receptor Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1PP presents examples of FKBP Receptor Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1QQ-1TT present examples of Androgen Receptor Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 1UU presents examples of Estrogen Receptor Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 1VV-1WW present examples of Thyroid Hormone Receptor TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1XX presents examples of HIV Protease Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1YY presents examples of HIV Integrase Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1ZZ presents examples of HCV Protease Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1AAA presents examples of AP1 and/or AP2 Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 1BBB-1CCC present examples of MCL-1 Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 1DDD presents examples of IDH1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1EEE-1FFF present examples of RAS or RASK Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 1GGG presents examples of MERTK or MER Targeting Ligands wherein Ris the point at which the linker is attached.

FIG. 1HHH-1III present examples of EGFR Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 1JJJ-1KKK present examples of FLT3 Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 1LLL presents examples of SMRCA2 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 2A presents examples of the kinase inhibitor Targeting LigandsU09-CX-5279 (derivatized) wherein R is the point at which the Linker isattached.

FIG. 2B-2C present examples of kinase inhibitor Targeting Ligands,including the kinase inhibitor compounds Y1W and Y1X (derivatized)wherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the kinase inhibitors identified inMillan et al. “Design and Synthesis of Inhaled P38 Inhibitors for theTreatment of Chronic Obstructive Pulmonary Disease” J. Med. Chem., 54:7797 (2011).

FIG. 2D presents examples of kinase inhibitor Targeting Ligands,including the kinase inhibitor compounds 6TP and 0TP (derivatized)wherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the kinase inhibitors identified inSchenkel et al. “Discovery of Potent and Highly Selective ThienopyridineJanus Kinase 2 Inhibitors” J. Med. Chem., 54 (24): 8440-8450 (2011).

FIG. 2E presents examples of kinase inhibitor Targeting Ligands,including the kinase inhibitor compound 07U wherein R is the point atwhich the Linker is attached. For additional examples and relatedligands, see, the kinase inhibitors identified in Van Eis et al. “26-Naphthyridines as potent and selective inhibitors of the novel proteinkinase C isozymes” Biorg. Med. Chem. Lett., 21(24): 7367-72 (2011).

FIG. 2F presents examples of kinase inhibitor Targeting Ligands,including the kinase inhibitor compound YCF, wherein R is the point atwhich the Linker is attached. For additional examples and relatedligands, see, the kinase inhibitors identified in Lountos et al.“Structural Characterization of Inhibitor Complexes with CheckpointKinase 2 (Chk2) a Drug Target for Cancer Therapy” J. Struct. Biol., 176:292 (2011).

FIG. 2G-2H present examples of kinase inhibitor Targeting Ligands,including the kinase inhibitors XK9 and NXP (derivatized) wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the kinase inhibitors identified in Lountos et al.“Structural Characterization of Inhibitor Complexes with CheckpointKinase 2 (Chk2) a Drug Target for Cancer Therapy” J. Struct. Biol., 176:292 (2011).

FIG. 2I-2J present examples of kinase inhibitor Targeting Ligandswherein R is the point at which the Linker r is attached.

FIG. 2K-2M present examples of Cyclin Dependent Kinase 9 (CDK9)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Baumli etal. “The structure of P-TEFb (CDK9/cyclin T1) its complex withflavopiridol and regulation by phosphorylation.” Embo J., 27: 1907-1918(2008); Bettayeb et al. “CDK Inhibitors Roscovitine and CR8 TriggerMcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells.”Genes Cancer, 1: 369-380 (2010); Baumi et al. “Halogen bonds form thebasis for selective P-TEFb inhibition by DRB.” Chem.Biol. 17: 931-936(2010); Hole et al. “Comparative Structural and Functional Studies of4-(Thiazol-5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9Inhibitors Suggest the Basis for Isotype Selectivity.” J.Med.Chem. 56:660 (2013); Lucking et al. “Identification of the potent and highlyselective PTEFb inhibitor BAY 1251152 for the treatment of cancer—Fromp.o. to i.v. application via scaffold hops.” Lucking et al. U. AACRAnnual Meeting, Apr. 1-5, 2017 Washington, D.C. USA.

FIG. 2N-2P present examples of Cyclin Dependent Kinase 4/6 (CDK4/6)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Lu H.;Schulze-Gahmen U.; “Toward understanding the structural basis ofcyclin-dependent kinase 6 specific inhibition.” J. Med. Chem., 49:3826-3831 (2006); 4-(Pyrazol-4-yl)-pyrimidines as selective inhibitorsof cyclin-dependent kinase 4/6. Cho et al. (2010) J.Med.Chem. 53:7938-7957; Cho Y. S. et al. “Fragment-Based Discovery of7-Azabenzimidazoles as Potent Highly Selective and Orally Active CDK4/6Inhibitors.” ACS Med Chem Lett 3: 445-449 (2012); Li Z. et al.“Discovery of AMG 925 a FLT3 and CDK4 dual kinase inhibitor withpreferential affinity for the activated state of FLT3.” J. Med. Chem.57: 3430-3449 (2014); Chen P. et al. “Spectrum and Degree of CDK DrugInteractions Predicts Clinical Performance.” Mol. Cancer Ther. 15:2273-2281 (2016).

FIG. 2Q presents examples of Cyclin Dependent Kinase 12 and/or CyclinDependent Kinase 13 Targeting Ligands wherein R is the point at whichthe Linker is attached. For additional examples and related ligands,see, Zhang T. et al. “Covalent Targeting of Remote Cysteine Residues toDevelop Cdkl2 and Cdkl3 Inhibitors.” Nat. Chem. Biol. 12: 876 (2016).

FIG. 2R-2S present examples of Glucocorticoid Receptor Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 2T-2U present examples of RasG12C Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 2V presents examples of Her3 Targeting Ligands wherein R is thepoint at which the Linker is attached and R′ is

FIG. 2W presents examples of Bcl-2 or Bcl-XL Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 2X-2NN present examples of BCL2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Toure B. B. et al. “The role of the acidity ofN-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-proteininteractions.” ACS Med Chem Lett, 4: 186-190 (2013); Porter J. et al.“Tetrahydroisoquinoline Amide Substituted Phenyl Pyrazoles as SelectiveBcl-2 Inhibitors” Bioorg. Med. Chem. Lett. 19: 230 (2009); Souers A. J.et al. “ABT-199 a potent and selective BCL-2 inhibitor achievesantitumor activity while sparing platelets.” Nature Med. 19: 202-208(2013); Angelo Aguilar et al. “A Potent and Highly EfficaciousBcl-2/Bcl-xL Inhibitor” J Med Chem. 56(7): 3048-3067 (2013); LongchuanBai et al. “BM-1197: A Novel and Specific Bcl-2/Bcl-xL InhibitorInducing Complete and Long-Lasting Tumor Regression In Vivo” PLoS ONE9(6): e99404; Fariba Ne'matil et al. “Targeting Bcl-2/Bcl-XL InducesAntitumor Activity in Uveal Melanoma Patient-Derived Xenografts” PLoSONE 9(1): e80836; WO2015011396 titled “Novel derivatives of indole andpyrrole method for the production thereof and pharmaceuticalcompositions containing same”; WO2008060569A1 titled “Compounds andmethods for inhibiting the interaction of Bcl proteins with bindingpartners”; “Inhibitors of the anti-apoptotic Bcl-2 proteins: a patentreview” Expert Opin. Ther. Patents 22(1):2008 (2012); and, Porter et al.“Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selectiveBcl-2 inhibitors” Bioorg Med Chem Lett., 19(1):230-3 (2009).

FIG. 2OO-2UU present examples of BCL-XL Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Zhi-Fu Tao et al. “Discovery of a Potent andSelective BCL-XL Inhibitor with in Vivo Activity” ACS Med. Chem. Lett.,5: 1088-1093 (2014); Joel D. Leverson et al. “Exploiting selective BCL-2family inhibitors to dissect cell survival dependencies and defineimproved strategies for cancer therapy” Science Translational Medicine,7:279ra40 (2015); and, the crystal structure PDB 3ZK6 (Guillaume Lesseneet al. “Structure-guided design of a selective BCL-XL inhibitor” NatureChemical Biology 9: 390-397 (2013))

FIG. 2VV presents examples of PPAR-gamma Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 2WW-2YY present examples of EGFR Targeting Ligands that target theEGFR L858R mutant, including erlotinib, gefitnib, afatinib, neratinib,and dacomitinib, wherein R is the point at which the Linker is attached.

FIG. 2ZZ-2FFF present examples of EGFR Targeting Ligands that target theEGFR T790M mutant, including osimertinib, rociletinib, olmutinib,naquotinib, nazartinib, PF-06747775, Icotinib, Neratinib Avitinib,Tarloxotinib, PF-0645998, Tesevatinib, Transtinib, WZ-3146, WZ8040, andCNX-2006, wherein R is the point at which the Linker is attached.

FIG. 2GGG presents examples of EGFR Targeting Ligands that target theEGFR C797S mutant, including EAI045, wherein R is the point at which theLinker is attached.

FIG. 2HHH presents examples of BCR-ABL Targeting Ligands that target theBCR-ABL T315I mutantm including Nilotinib and Dasatinib, wherein R isthe point at which the Linker is attached. See for example, the crystalstructure PDB 3CS9.

FIG. 2III presents examples of Targeting Ligands that target BCR-ABL,including Nilotinib, Dasatinib Ponatinib and Bosutinib, wherein R is thepoint at which the Linker is attached.

FIG. 2JJJ-2KKK present examples of ALK Targeting Ligands that target theALK L1196M mutant including Ceritinib, wherein R is the point at whichthe Linker is attached. See for example, the crystal structure PDB 4MKC.

FIG. 2LLL presents examples of JAK2 Targeting Ligands that target theJAK2V617F mutant, including Ruxolitinib, wherein R is the point at whichthe Linker is attached.

FIG. 2MMM presents examples of BRAF Targeting Ligands that target theBRAF V600E mutant including Vemurafenib, wherein R is the point at whichthe Linker is attached. For additional examples and related ligands,see, the crystal structure PBD 3OG7.

FIG. 2NNN presents examples of BRAF Targeting Ligands, includingDabrafenib, wherein R is the point at which the Linker is attached.

FIG. 2OOO presents examples of LRRK2 Targeting Ligands that target theLRRK2 R1441C mutant wherein R is the point at which the Linker isattached.

FIG. 2PPP presents examples of LRRK2 Targeting Ligands that target theLRRK2 G2019S mutant wherein R is the point at which the Linker isattached.

FIG. 2QQQ presents examples of LRRK2 Targeting Ligands that target theLRRK2 I2020T mutant wherein R is the point at which the Linker isattached.

FIG. 2RRR-2TTT present examples of PDGFRα Targeting Ligands that targetthe PDGFRα T674I mutant, including AG-1478, CHEMBL94431, Dovitinib,erlotinib, gefitinib, imatinib, Janex 1, Pazopanib, PD153035, Sorafenib,Sunitinib, and WHI-P180, wherein R is the point at which the Linker isattached.

FIG. 2UUU presents examples of RET Targeting Ligands that target the RETG691S mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2VVV presents examples of RET Targeting Ligands that target the RETR749T mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2WWW presents examples of RET Targeting Ligands that target the RETE762Q mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2XXX presents examples of RET Targeting Ligands that target the RETY791F mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2YYY presents examples of RET Targeting Ligands that target the RETV804M mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2ZZZ presents examples of RET Targeting Ligands that target the RETM918T mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2AAAA presents examples of Fatty Acid Binding Protein TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2BBBB presents examples of 5-Lipoxygenase Activating Protein (FLAP)Targeting Ligands wherein R is the point at which the Linker isattached.

FIG. 2CCCC presents examples of Kringle Domain V 4BVV Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 2DDDD presents examples of Lactoylglutathione Lyase TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2EEEE-2FFFF present examples of mPGES-1 Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 2GGGG-2JJJJ present examples of Factor Xa Targeting Ligands whereinR is the point at which the Linker is attached. For additional examplesand related ligands, see, Maignan S. et al. “Crystal structures of humanfactor Xa complexed with potent inhibitors.” J. Med Chem. 43: 3226-3232(2000); Matsusue T. et al. “Factor Xa Specific Inhibitor that Inducesthe Novel Binding Model in Complex with Human Fxa.” (to be published);the crystal structures PDB 1iqh, 1iqi, 1iqk, and 1igm; Adler M. et al.“Crystal Structures of Two Potent Nonamidine Inhibitors Bound to FactorXa.” Biochemistry 41: 15514-15523 (2002); Roehrig S. et al. “Discoveryof the Novel Antithrombotic Agent5-Chloro-N-({(5S)-2-Oxo-3-[4-(3-Oxomorpholin-4-Yl)Phenyl]-13-Oxazolidin-5-Yl}Methyl)Thiophene-2-Carboxamide (Bay 59-7939): An OralDirect Factor Xa Inhibitor.” J. Med Chem. 48: 5900 (2005); Anselm L. etal. “Discovery of a Factor Xa Inhibitor (3R 4R)-1-(22-Difluoro-Ethyl)-Pyrrolidine-3 4-Dicarboxylic Acid3-[(5-Chloro-Pyridin-2-Yl)-Amide]4-{[2-Fluoro-4-(2-Oxo-2H-Pyridin-1-Yl)-Phenyl]-Amide} as a ClinicalCandidate.” Bioorg. Med Chem. 20: 5313 (2010); and, Pinto D. J. et al.“Discovery of1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4 5 67-tetrahydro-1H-pyrazolo[3 4-c]pyridine-3-carboxamide (ApixabanBMS-562247) a Highly Potent Selective Efficacious and OrallyBioavailable Inhibitor of Blood Coagulation Factor Xa.” J. Med Chem. 50:5339-5356 (2007).

FIG. 2KKKK presents examples of Kallikrein 7 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, Maibaum J. et al. “Small-molecule factor Dinhibitors targeting the alternative complement pathway.” Nat. Chem.Biol. 12: 1105-1110 (2016).

FIG. 2LLLL-2MMMM present examples of Cathepsin K Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, Rankovic Z. et al. “Design andoptimization of a series of novel 2-cyano-pyrimidines as cathepsin Kinhibitors” Bioorg. Med Chem. Lett. 20: 1524-1527 (2010); and, Cai J. etal. “Trifluoromethylphenyl as P2 for ketoamide-based cathepsin Sinhibitors.” Bioorg. Med Chem. Lett. 20: 6890-6894 (2010).

FIG. 2NNNN presents examples of Cathepsin L Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, Kuhn B. et al. “Prospective Evaluation of FreeEnergy Calculations for the Prioritization of Cathepsin L Inhibitors.”J. Med Chem. 60: 2485-2497 (2017).

FIG. 2OOOO presents examples of Cathepsin S Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, Jadhav P. K. et al. “Discovery of Cathepsin SInhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm” ACSMed Chem. Lett. 5: 1138-1142.” (2014).

FIG. 2PPPP-2SSSS present examples of MTH1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Kettle J. G. et al. “Potent and SelectiveInhibitors of Mth1 Probe its Role in Cancer Cell Survival.” J. Med Chem.59: 2346 (2016); Huber K. V. M. et al. “Stereospecific Targeting of Mth1by (S)-Crizotinib as an Anticancer Strategy.” Nature 508: 222 (2014);Gad H. et al. “MTH1 inhibition eradicates cancer by preventingsanitation of the dNTP pool.” Nature 508: 215-221 (2014); Nissink J. W.M. et al. “Mth1 Substrate Recognition—an Example of SpecificPromiscuity.” Plos One 11: 51154 (2016); and, Manuel Ellermann et al.“Novel class of potent and selective inhibitors efface MTH1 asbroad-spectrum cancer target.” AACR National Meeting Abstract 5226,2017.

FIG. 2TTTT-2ZZZZ present examples of MDM2 and/or MDM4 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, Popowicz G. M. et al. “Structures oflow molecular weight inhibitors bound to MDMX and MDM2 reveal newapproaches for p53-MDMX/MDM2 antagonist drug discovery.” Cell Cycle, 9(2010); Miyazaki M. et al. “Synthesis and evaluation of novel orallyactive p53-MDM2 interaction inhibitors.” Bioorg. Med Chem. 21: 4319-4331(2013); Miyazaki M. et al. “Discovery of DS-5272 as a promisingcandidate: A potent and orally active p53-MDM2 interaction inhibitor.”Bioorg Med Chem. 23: 2360-7 (2015); Holzer P. et al. “Discovery of aDihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent andSelective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53 wtTumors.” J. Med Chem. 58: 6348-6358 (2015); Gonzalez-Lopez de Turiso F.et al. “Rational Design and Binding Mode Duality of MDM2-p53Inhibitors.” J. Med. Chem. 56: 4053-4070 (2013); Gessier F. et al.“Discovery of dihydroisoquinolinone derivatives as novel inhibitors ofthe p53-MDM2 interaction with a distinct binding mode.” Bioorg. MedChem. Lett. 25: 3621-3625 (2015); Fry D.C. et al. “Deconstruction of anutlin: dissecting the binding determinants of a potent protein-proteininteraction inhibitor.” ACS Med Chem Lett 4: 660-665 (2013); Ding Q. etal. “Discovery of RG7388 a Potent and Selective p53-MDM2 Inhibitor inClinical Development.” J. Med Chem. 56: 5979-5983 (2013); Wang S. et al.“SAR405838: an optimized inhibitor of MDM2-p53 interaction that inducescomplete and durable tumor regression.” Cancer Res. 74: 5855-5865(2014); Rew Y. et al. “Discovery of AM-7209 a Potent and Selective4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.” J. Med Chem.57: 10499-10511 (2014); Bogen S. L. et al. “Discovery of Novel 33-Disubstituted Piperidines as Orally Bioavailable Potent andEfficacious HDM2-p53 Inhibitors.” ACS Med Chem. Lett. 7: 324-329 (2016);and, Sun D. et al. “Discovery of AMG 232 a Potent Selective and OrallyBioavailable MDM2-p53 Inhibitor in Clinical Development.” J Med Chem.57: 1454-1472 (2014).

FIG. 2AAAAA-2EEEEE present examples of PARP1, PARP2, and/or PARP3Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Iwashita A.et al. “Discovery of quinazolinone and quinoxaline derivatives as potentand selective poly(ADP-ribose) polymerase-1/2 inhibitors.” Febs Lett.579: 1389-1393 (2005); the crystal structure PDB 2RCW (PARP complexedwith A861695, Park C. H.); the crystal structure PDB 2RD6 (PARPcomplexed with A861696, Park C. H.); the crystal structure PDB 3GN7;Miyashiro J. et al. “Synthesis and SAR of novel tricyclic quinoxalinoneinhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)” Bioorg. Med Chem.Lett. 19: 4050-4054 (2009); Gandhi V. B. et al. “Discovery and SAR ofsubstituted 3-oxoisoindoline-4-carboxamides as potent inhibitors ofpoly(ADP-ribose) polymerase (PARP) for the treatment of cancer.” Bioorg.Med Chem. Lett. 20: 1023-1026 (2010); Penning T. D. et al. “Optimizationof phenyl-substituted benzimidazole carboxamide poly(ADP-ribose)polymerase inhibitors: identification of(S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide(A-966492) a highly potent and efficacious inhibitor.” J. Med Chem. 53:3142-3153 (2010); Ye N. et al. “Design, Synthesis, and BiologicalEvaluation of a Series of Benzo[de][1 7]naphthyridin-7(8H)-ones Bearinga Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors.” J.Med Chem. 56: 2885-2903 (2013); Patel M. R. et al. “Discovery andStructure-Activity Relationship of Novel 23-Dihydrobenzofuran-7-carboxamide and 23-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives asPoly(ADP-ribose)polymerase-1 Inhibitors.” J. Med Chem. 57: 5579-5601(2014); Thorsell A. G. et al. “Structural Basis for Potency andPromiscuity in Poly(ADP-ribose) Polymerase (PARP) and TankyraseInhibitors.” J. Med Chem. 60:1262-1271 (2012); the crystal structure PDB4RV6 (“Human ARTD1 (PARP1) catalytic domain in complex with inhibitorRucaparib”, Karlberg T. et al.); Papeo G. M. E. et al. “Discovery of2-[1-(4 4-Difluorocyclohexyl)Piperidin-4-Yl]-6-Fluoro-3-Oxo-23-Dihydro-1H-Isoindole-4-Carboxamide (Nms-P118): A Potent OrallyAvailable and Highly Selective Parp-1 Inhibitor for Cancer Therapy.” J.Med. Chem. 58: 6875 (2015); Kinoshita T. et al. “Inhibitor-inducedstructural change of the active site of human poly(ADP-ribose)polymerase.” Febs Lett. 556: 43-46 (2004); and, Gangloff A. R. et al.“Discovery of novel benzo[b][1 4]oxazin-3(4H)-ones aspoly(ADP-ribose)polymerase inhibitors.” Bioorg. Med. Chem. Lett. 23:4501-4505 (2013).

FIG. 2FFFFF-2GGGGG present examples of PARP14 Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 2HHHHH presents examples of PARP15 Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 2IIIII presents examples of PDZ domain Targeting Ligands wherein Ris the point at which the Linker(s) are attached.

FIG. 2JJJJJ presents examples of Phospholipase A2 domain TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2KKKKK presents examples of Protein S100-A7 2WOS Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 2LLLLL-2MMMMM present examples of Saposin-B Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 2NNNNN-2OOOOO present examples of Sec7 Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 2PPPPP-2QQQQQ present examples of SH2 domain of pp60 Src TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2RRRRR presents examples of Tank1 Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 2SSSSS presents examples of Ubc9 SUMO E2 ligase SF6D TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2TTTTT presents examples of Src Targenting Ligands, includingAP23464, wherein R is the point at which the Linker is attached.

FIG. 2UUUUU-2XXXXX present examples of Src-AS1 and/or Src AS2 TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2YYYYY presents examples of JAK3 Targeting Ligands, includingTofacitinib, wherein R is the point at which the Linker is attached.

FIG. 2ZZZZZ presents examples of ABL Targeting Ligands, includingTofacitinib and Ponatinib, wherein R is the point at which the Linker isattached.

FIG. 3A-3B present examples of MEK1 Targeting Ligands, includingPD318088, Trametinib and G-573, wherein R is the point at which theLinker is attached.

FIG. 3C presents examples of KIT Targeting Ligands, includingRegorafenib, wherein R is the point at which the Linker is attached.

FIG. 3D-3E present examples of HIV Reverse Transcriptase TargetingLigands, including Efavirenz, Tenofovir, Emtricitabine, Ritonavir,Raltegravir, and Atazanavir, wherein R is the point at which the Linkeris attached.

FIG. 3F-3G present examples of HIV Protease Targeting Ligands, includingRitonavir, Raltegravir, and Atazanavir, wherein R is the point at whichthe Linker is attached.

FIG. 311-3I present examples of KSR1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3J-3L present examples of CNNTB1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3M presents examples of BCL6 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3N-3O present examples of PAK1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3P-3R present examples of PAK4 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3S-3T present examples of TNIK Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3U presents examples of MEN1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3V-3W present examples of ERK1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3X presents examples of IDO1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3Y presents examples of CBP Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3Z-3SS present examples of MCL1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Tanaka Y. et al “Discovery of potent Mcl-1/Bcl-xLdual inhibitors by using a hybridization strategy based on structuralanalysis of target proteins.” J. Med Chem. 56: 9635-9645 (2013); FribergA. et al. “Discovery of potent myeloid cell leukemia 1 (Mcl-1)inhibitors using fragment-based methods and structure-based design.” J.Med Chem. 56: 15-30 (2013); Petros A. M. et al “Fragment-based discoveryof potent inhibitors of the anti-apoptotic MCL-1 protein.” Bioorg. MedChem. Lett. 24: 1484-1488 (2014); Burke J. P. et al. “Discovery oftricyclic indoles that potently inhibit mcl-1 using fragment-basedmethods and structure-based design.” J. Med. Chem. 58: 3794-3805 (2015);Pelz N. F. et al. “Discovery of 2-Indole-acylsulfonamide Myeloid CellLeukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.” J. MedChem. 59: 2054-2066 (2016); Clifton M. C. et al. “A Maltose-BindingProtein Fusion Construct Yields a Robust Crystallography Platform forMCL1.” Plos One 10: e0125010-e0125010 (2015); Kotschy A et al. “The MCL1inhibitor S63845 is tolerable and effective in diverse cancer models.Nature 538:477-482 (2016); EP 2886545 A1 titled “New thienopyrimidinederivatives a process for their preparation and pharmaceuticalcompositions containing them”; Jeffrey W. Johannes et al. “StructureBased Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors” ACSMed Chem. Lett. (2017); DOI: 10.1021/acsmedchemlett.6b00464; Bruncko M.et al. “Structure-Guided Design of a Series of MCL-1 Inhibitors withHigh Affinity and Selectivity.” J. Med Chem. 58: 2180-2194 (2015);Taekyu Lee et al. “Discovery and biological characterization of potentmyeloid cell leukemia-1 inhibitors.” FEBS Letters 591: 240-251 (2017);Chen L. et al. “Structure-Based Design of 3-Carboxy-Substituted 1 2 34-Tetrahydroquinolines as Inhibitors of Myeloid Cell Leukemia-1(Mcl-1).” Org. Biomol. Chem. 14:5505-5510 (2016); US 2016/0068545 titled“Tetrahydronaphthalene derivatives that inhibit mcl-1 protein”; WO2016207217 A1 titled “Preparation of new bicyclic derivatives aspro-apoptotic agents”; Gizem Akgay et al. “Inhibition of Mcl-1 throughcovalent modification of a noncatalytic lysine side chain” NatureChemical Biology 12: 931-936 (2016).

FIG. 3TT presents examples of ASH1L Targeting Ligands wherein R is thepoint at which the Linker is attached. See for example, the crystalstructure PDB 4YNM (“Human ASH1L SET domain in complex with S-adenosylmethionine (SAM)” Rogawski D. S. et al.)

FIG. 3UU-3WW present examples of ATAD2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Chaikuad A. et al. “Structure-based approachestowards identification of fragments for the low-druggability ATAD2bromodomain” Med Chem Comm 5: 1843-1848 (2014); Poncet-Montange G. etal. “Observed bromodomain flexibility reveals histone peptide- and smallmolecule ligand-compatible forms of ATAD2.” Biochem. J. 466: 337-346(2015); Harner M. J. et al. “Fragment-Based Screening of the Bromodomainof ATAD2.” J. Med Chem. 57: 9687-9692 (2014); Demont E. H. et al.“Fragment-Based Discovery of Low-Micromolar Atad2 BromodomainInhibitors.” J. Med Chem. 58: 5649 (2015); and, Bamborough P. et al.“Structure-Based Optimization of Naphthyridones into Potent Atad2Bromodomain Inhibitors.” J. Med Chem. 58: 6151 (2015).

FIG. 3XX-3AAA present examples of BAZ2A and BAZ2B Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structure PDB 4CUU(“Human Baz2B in Complex with Fragment-6 N09645” Bradley A. et al.); thecrystal structure PDB 5CUA (“Second Bromodomain of Bromodomain Adjacentto Zinc Finger Domain Protein 2B (BAZ2B) in complex with1-Acetyl-4-(4-hydroxyphenyl)piperazine”. Bradley A. et al.); Ferguson F.M. et al. “Targeting low-druggability bromodomains: fragment basedscreening and inhibitor design against the BAZ2B bromodomain.” J. MedChem. 56: 10183-10187 (2013); Marchand J. R. et al. “Derivatives of3-Amino-2-methylpyridine as BAZ2B Bromodomain Ligands: In SilicoDiscovery and in Crystallo Validation.” J. Med Chem. 59: 9919-9927(2016); Drouin L. et al. “Structure Enabled Design of BAZ2-ICR AChemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B.” J. MedChem. 58: 2553-2559 (2015); Chen P. et al. “Discovery andcharacterization of GSK2801 a selective chemical probe for thebromodomains BAZ2A and BAZ2B.” J. Med Chem. 59:1410-1424 (2016).

FIG. 3BBB presents examples of BRD1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 5AME (“the CrystalStructure of the Bromodomain of Human Surface Epitope Engineered Brd1Ain Complex with 3D Consortium Fragment 4-Acetyl-Piperazin-2-One Pearce”,N.M. et al.); the crystal structure PDB 5AMF (“Crystal Structure of theBromodomain of Human Surface Epitope Engineered Brd1A in Complex with 3DConsortium Fragment Ethyl 4 5 6 7-Tetrahydro-1H-Indazole-5-Carboxylate”,Pearce N. M. et al.); the crystal structure PDB 5FG6 (“the Crystalstructure of the bromodomain of human BRD1 (BRPF2) in complex with OF-1chemical probe.”, Tallant C. et al.); Filippakopoulos P. et al. “Histonerecognition and large-scale structural analysis of the human bromodomainfamily.” Cell, 149: 214-231 (2012).

FIG. 3CCC-3EEE present examples of BRD2 Bromodomain 1 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structure PDB 2ydw; thecrystal structure PDB 2yek; the crystal structure PDB 4a9h; the crystalstructure PDB 4a9f; the crystal structure PDB 4a9i; the crystalstructure PDB 4a9m; the crystal structure PDB 4akn; the crystalstructure PDB 4alg, and the crystal structure PDB 4uyf.

FIG. 3FFF-3HHH present examples of BRD2 Bromodomain 2 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structure PDB 3oni;Filippakopoulos P. et al. “Selective Inhibition of BET Bromodomains.”Nature 468: 1067-1073 (2010); the crystal structure PDB 4jlp; McLure K.G. et al. “RVX-208: an Inducer of ApoA-I in Humans is a BET BromodomainAntagonist.” Plos One 8: e83190-e83190 (2013); Baud M. G. et al.“Chemical biology. A bump-and-hole approach to engineer controlledselectivity of BET bromodomain chemical probes” Science 346: 638-641(2014); Baud M. G. et al. “New Synthetic Routes toTriazolo-benzodiazepine Analogues: Expanding the Scope of theBump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET)Bromodomain Inhibition” J. Med. Chem. 59: 1492-1500 (2016); Gosmini R.et al. “The Discovery of I-Bet726 (Gsk1324726A) a PotentTetrahydroquinoline Apoa1 Up-Regulator and Selective Bet BromodomainInhibitor” J. Med. Chem. 57: 8111 (2014); the crystal structure PDB 5EK9(“Crystal structure of the second bromodomain of human BRD2 in complexwith a hydroquinolinone inhibitor”, Tallant C. et al); the crystalstructure PDB 5BT5; the crystal structure PDB 5dfd; Baud M. G. et al.“New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expandingthe Scope of the Bump-and-Hole Approach for Selective Bromo andExtra-Terminal (BET) Bromodomain Inhibition” J. Med. Chem. 59: 1492-1500(2016).

FIG. 3III-3JJJ present examples of BRD4 Bromodomain 1 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structure PDB 5WUU andthe crystal structure PDB 5F5Z.

FIG. 3KKK-3LLL present examples of BRD4 Bromodomain 2 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, Chung C. W. et al. “Discovery andCharacterization of Small Molecule Inhibitors of the Bet FamilyBromodomains” J. Med. Chem. 54: 3827 (2011) and Ran X. et al.“Structure-Based Design of gamma-Carboline Analogues as Potent andSpecific BET Bromodomain Inhibitors” J. Med. Chem. 58: 4927-4939 (2015).

FIG. 3MMM presents examples of BRDT Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 4flp and the crystalstructure PDB 4kcx.

FIG. 3NNN-3QQQ present examples of BRD9 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 4ngn; the crystalstructure PDB 4uit; the crystal structure PDB 4uiu; the crystalstructure PDB 4uiv; the crystal structure PDB 4z6h; the crystalstructure PDB 4z6i; the crystal structure PDB 5e9v; the crystalstructure PDB 5eul; the crystal structure PDB 5flh; and, the crystalstructure PDB 5fp2.

FIG. 3RRR presents examples of SMARCA4 PB1 and/or SMARCA2 TargetingLigands wherein R is the point at which the Linker is attached, A is Nor CH, and m is 0 1 2 3 4 5 6 7 or 8.

FIG. 3SSS-3XXX present examples of additional Bromodomain TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, Hewings et al. “35-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands.” J. Med.Chem. 54 6761-6770 (2011); Dawson et al. “Inhibition of BET Recruitmentto Chromatin as an Effective Treatment for MLL-fusion Leukemia.” Nature,478, 529-533 (2011); US 2015/0256700; US 2015/0148342; WO 2015/074064;WO 2015/067770; WO 2015/022332; WO 2015/015318; and, WO 2015/011084.

FIG. 3YYY presents examples of PB1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3mb4; the crystalstructure PDB 4qOn; and, the crystal structure PDB 5fh6.

FIG. 3ZZZ presents examples of SMARCA4 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure 3uvd and the crystalstructure 5dkd.

FIG. 3AAAA presents examples of SMARCA2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure 5dkc and the crystalstructure 5dkh.

FIG. 3BBBB presents examples of TRIM24 (TIF1a) and/or BRPF1 TargetingLigands wherein R is the point at which the Linker is attached and m is0 1 2 3 4 5 6 7 or 8.

FIG. 3CCCC presents examples of TRIM24 (TIF1a) Targeting Ligands whereinR is the point at which the Linker is attached. For additional examplesand related ligands, see, Palmer W. S. et al. “Structure-Guided Designof IACS-9571: a Selective High-Affinity Dual TRIM24-BRPF1 BromodomainInhibitor.” J. Med. Chem. 59: 1440-1454 (2016).

FIG. 3DDDD-3FFFF present examples of BRPF1 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 4uye; the crystalstructure PDB 5c7n; the crystal structure PDB 5c87; the crystalstructure PDB 5c89; the crystal structure PDB 5d7x; the crystalstructure PDB 5dya; the crystal structure PDB 5epr; the crystalstructure PDB 5eql; the crystal structure PDB 5etb; the crystalstructure PDB 5ev9; the crystal structure PDB 5eva; the crystalstructure PDB 5ewv; the crystal structure PDB 5eww; the crystalstructure PDB 5ffy; the crystal structure PDB 5fg5; and, the crystalstructure PDB 5g4r.

FIG. 3GGGG presents examples of CECR2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Moustakim M. et al. Med. Chem. Comm. 7:2246-2264(2016) and Crawford T. et al. Journal of Med. Chem. 59; 5391-5402(2016).

FIG. 3HHHH-3OOOO present examples of CREBBP Targeting Ligands wherein Ris the point at which the Linker is attached, A is N or CH, and m is 0 12 3 4 5 6 7 or 8. For additional examples and related ligands, see, thecrystal structure PDB 3pld; the crystal structure PDB 3svh; the crystalstructure PDB 4nr4; the crystal structure PDB 4nr5; the crystalstructure PDB 4ts8; the crystal structure PDB 4nr6; the crystalstructure PDB 4nr7; the crystal structure PDB 4nyw; the crystalstructure PDB 4nyx; the crystal structure PDB 4tqn; the crystalstructure PDB 5cgp; the crystal structure PDB 5dbm; the crystalstructure PDB 5ep7; the crystal structure PDB 5i83; the crystalstructure PDB 5i86; the crystal structure PDB 5i89; the crystalstructure PDB 5i8g; the crystal structure PDB 5jOd; the crystalstructure PDB 5ktu; the crystal structure PDB 5ktw; the crystalstructure PDB 5ktx; the crystal structure PDB 5tb6.

FIG. 3PPPP presents examples of EP300 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 5BT3.

FIG. 3QQQQ presents examples of PCAF Targeting Ligands wherein R is thepoint at which the Linker is attached. See for example, M. Ghizzoni etal. Bioorg. Med Chem. 18: 5826-5834 (2010).

FIG. 3RRRR presents examples of PHIP Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Mol Cancer Ther. 7(9): 2621-2632 (2008).

FIG. 3SSSS presents examples of TAF1 and TAF1L Targeting Ligands whereinR is the point at which the Linker is attached. For additional examplesand related ligands, see, Picaud S. et al. Sci Adv 2: e1600760-e1600760(2016).

FIG. 3TTTT presents examples of Histone Deacetylase 2 (HDAC2) TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, Lauffer B. E. J. Biol.Chem. 288: 26926-26943 (2013); Wagner F. F. Bioorg. Med Chem. 24:4008-4015 (2016); Bressi J. C. Bioorg. Med Chem. Lett. 20: 3142-3145(2010); and, Lauffer B. E. J. Biol. Chem. 288: 26926-26943 (2013).

FIG. 3UUUU-3VVVV present examples of Histone Deacetylase 4 (HDAC4)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Burli R. W.J. Med Chem. 56: 9934 (2013); Luckhurst C. A. ACS Med Chem. Lett. 7: 34(2016); Bottomley M. J. J. Biol. Chem. 283: 26694-26704 (2008).

FIG. 3WWWW presents examples of Histone Deaceytlase 6 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, Harding R. J. (to be published); HaiY. Nat. Chem. Biol. 12: 741-747, (2016); and, Miyake Y. Nat. Chem. Biol.12: 748 (2016).

FIG. 3XXXX-3YYYY presents examples of Histone Deacetylase 7 TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, Lobera M. Nat. Chem. Biol.9: 319 (2013) and Schuetz A. J. Biol. Chem. 283: 11355-11363 (2008).

FIG. 3ZZZZ-3DDDDD present examples of Histone Deacetylase 8 TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, Whitehead L. Biol. MedChem. 19: 4626-4634 (2011); Tabackman A. A. J. Struct. Biol. 195:373-378 (2016); Dowling D. P. Biochemistry 47, 13554-13563 (2008);Somoza J. R. Biochemistry 12, 1325-1334 (2004); Decroos C. Biochemistry54: 2126-2135 (2015); Vannini A. Proc. Natl Acad Sci. 101: 15064 (2004);Vannini A. EMBO Rep. 8: 879 (2007); the crystal structure PDB 5BWZ;Decroos A. ACS Chem. Biol. 9: 2157-2164 (2014); Somoza J. R.Biochemistry 12: 1325-1334 (2004); Decroos C. Biochemistry 54: 6501-6513(2015); Decroos A. ACS Chem. Biol. 9: 2157-2164 (2014); and, Dowling D.P. Biochemistry 47: 13554-13563 (2008).

FIG. 3EEEEE presents examples of Histone Acetyltransferase (KAT2B)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Chaikuad A.J. Med Chem. 59: 1648-1653 (2016); the crystal structure PDB 1ZS5; and,Zeng L. J. Am. Chem. Soc. 127: 2376-2377 (2005).

FIG. 3FFFFF-3GGGGG present examples of Histone Acetyltransferase (KAT2A)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Ringel A. E.Acta Crystallogr. D. Struct. Biol. 72: 841-848 (2016).

FIG. 3HHHHH presents examples of Histone Acetyltransferase Type BCatalytic Unit (HAT1) Targeting Ligands wherein R is the point at whichthe Linker is attached. For additional examples and related ligands,see, the crystal structure PDB 2POW.

FIG. 3IIIII presents examples of Cyclic AMP-dependent TranscriptionFactor (ATF2) Targeting Ligands wherein R is the point at which theLinker is attached.

FIG. 3JJJJJ presents examples of Histone Acetyltransferase (KAT5)Targeting Ligands wherein R is the point at which the Linker isattached.

FIG. 3KKKKK-3MMMMM present examples of Lysine-specific histonedemethylase 1A (KDM1A) Targeting Ligands wherein R is the point at whichthe Linker is attached. For additional examples and related ligands,see, Mimasu S. Biochemistry 49: 6494-6503 (2010); Sartori L. J. MedChem. 60:1673-1693 (2017); and, Vianello P. J. Med Chem. 60: 1693-1715(2017).

FIG. 3NNNNN presents examples of HDAC6 Zn Finger Domain TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 3OOOOO-3PPPPP present examples of general Lysine MethyltransferaseTargeting Ligands wherein R is the point at which the Linker isattached.

FIG. 3QQQQQ-3TTTTT present examples of DOTIL Targeting Ligands wherein Ris the point at which the Linker is attached, A is N or CH, and m is 0 12 3 4 5 6 7 or 8. For additional examples and related ligands, see, thecrystal structure PDB 5MVS (“Dot1L in complex with adenosine andinhibitor CPD1” Be C. et al.); the crystal structure PDB 5MW4 (“Dot1L incomplex inhibitor CPD7” Be C. et al.); the crystal structure PDB 5DRT(“Dot1L in complex inhibitor CPD2” Be C. et al.); Be C. et al. ACS Med.Lett. 8: 338-343 (2017); the crystal structure PDB 5JUW “(Dot1L incomplex with SS148” Yu W. et al. Structural Genomics Consortium).

FIG. 3UUUUU presents examples of EHMT1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 5TUZ (“EHMT1 in complexwith inhibitor MS0124”, Babault N. et al.).

FIG. 3VVVVV presents examples of EHMT2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 5TUY (“EHMT2 in complexwith inhibitor MS0124”, Babault N. et al.); the PDB crystal structure5TTF (“EHMT2 in complex with inhibitor MS012”, Dong A. et al.); the PDBcrystal structure 3RJW (Dong A. et al., Structural Genomics Consortium);the PDB crystal structure 3K5K; Liu F. et al. J. Med. Chem. 52:7950-7953 (2009); and, the PDB crystal structure 4NVQ (“EHMT2 in complexwith inhibitor A-366” Sweis R. F. et al.).

FIG. 3WWWWW presents examples of SETD2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5LSY (“SETD2 in complexwith cyproheptadine”, Tisi D. et al.); Tisi D. et al. ACS Chem. Biol.11: 3093-3105 (2016); the crystal structures PDB 5LSS, 5LSX, 5LSZ, 5LT6,5LT7, and 5LT8; the PDB crystal structure 4FMU; and, Zheng W. et al. J.Am. Chem. Soc. 134: 18004-18014 (2012).

FIG. 3XXXXX-3YYYYY present examples of SETD7 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the PDB crystal structure 5AYF (“SETD7 incomplex with cyproheptadine.” Niwa H. et al.); the PDB crystal structure4JLG (“SETD7 in complex with (R)-PFI-2”, Dong A. et al.); the PDBcrystal structure 4JDS (Dong A. et. al Structural Genomics Consortium);the PDB crystal structure 4E47 (Walker J. R. et al. Structural GenomicsConsortium; the PDB crystal structure 3VUZ (“SETD7 in complex withAAM-1.” Niwa H. et al.); the PDB crystal structure 3VVO; and, Niwa H etal. Acta Crystallogr. Sect. D 69: 595-602 (2013).

FIG. 3ZZZZZ presents examples of SETD8 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5TH7 (“SETD8 in complexwith MS453”, Yu W. et al.) and the PDB crystal structure 5T5G (Yu W et.al.; to be published).

FIG. 4A-4B present examples of SETDB1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5KE2 (“SETDB1 in complexwith inhibitor XST06472A”, Iqbal A. et al.); the PDB crystal structure5KE3 (“SETDB1 in complex with fragment MRT0181a”, Iqbal A. et al.); thePDB crystal structure 5KH6 (“SETDB1 in complex with fragment methyl3-(methylsulfonylamino)benzoate”, Walker J. R. et al. StructuralGenomics Consortium); and, the PDB crystal structure 5KCO (“SETDB1 incomplex with [N]-(4-chlorophenyl)methanesulfonamide”, Walker J. R. etal.)

FIG. 4C-4P present examples of SMYD2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5KJK (“SMYD2 in complexwith inhibitor AZ13450370”, Cowen S.D. et al.); the PDB crystalstructure 5KJM (“SMYD2 in complex with AZ931”, Cowen S.D. et al.); thePDB crystal structure 5KJN (“SMYD2 in complex with AZ506”, Cowen S.D. etal.); the PDB crystal structure 5ARF (“SMYD2 in complex withN-[3-(4-chlorophenyl)-1-{N′-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl}-45-dihydro-1H-pyrazol-4-YL]-N-ethyl-2-hydroxyacetamide”, Eggert E. etal.); the PDB crystal structure 5ARG (“SMYD2 in complex with BAY598”,Eggert E. et al.); the PDB crystal structure 4YND (“SMYD2 in complexwith A-893”, Sweis R. F. et al.); the PDB crystal structure 4WUY (“SMYD2in complex with LLY-507”, Nguyen H. et al.); and, the PDB crystalstructure 3S7B (“N-cyclohexyl-N˜3˜-[2-(34-dichlorophenyl)ethyl]-N-(2-{[2-(5-hydroxy-3-oxo-3 4-dihydro-2H-14-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide”, Ferguson A.D. etal.).

FIG. 4Q-4R present examples of SMYD3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure 5H17 (“SMYD3 in complex with5′-{[(3S)-3-amino-3-carboxypropyl][3-(dimethylamino)propyl]amino}-5′-deoxyadenosine”,Van Aller G. S. et al.); the crystal structure 5CCL (“SMYD3 in complexwith oxindole compound”, Mitchell L. H. et al.); and, the crystalstructure 5CCM (“Crystal structure of SMYD3 with SAM and EPZ030456”).

FIG. 4S presents examples of SUV4-20H1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5CPR (“SUV4-20H1 incomplex with inhibitor A-196”, Bromberg K.D. et al.).

FIG. 4T-4AA present examples of Wild Type Androgen Receptor TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, the PDB crystal structures5T8E and 5T8J (“Androgen Receptor in complex with4-(pyrrolidin-1-yl)benzonitrile derivatives”, Asano M. et al.); Asano M.et al. Bioorg. Med Chem. Lett. 27: 1897-1901 (2017); the PDB crystalstructure 5JJM (“Androgen Receptor”, Nadal M. et al.); the PDB crystalstructure 5CJ6 (“Androgen Receptor in complex with 2-Chloro-4-[[(1R2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrilederivatives”, Saeed A. et al.); the PDB crystal structure 4QL8(“Androgen Receptor in complex with 3-alkoxy-pyrrolo[1 2-b]pyrazolinesderivatives”, Ullrich T. et al.); the PDB crystal structure 4HLW(“Androgen Receptor Binding Function 3 (BF3) Site of the Human AndrogenReceptor through Virtual Screening”, Munuganti R. S. et al.); the PDBcrystal structure 3V49 (“Androgen Receptor lbd with activator peptideand sarm inhibitor 1”, Nique F. et al.); Nique F. et al. J. Med Chem.55: 8225-8235 (2012); the PDB crystal structure 2YHD (“Androgen Receptorin complex with AF2 small molecule inhibitor”, Axerio-Cilies P. et al.);the PDB crystal structure 3RLJ (“Androgen Receptor ligand binding domainin complex with SARM S-22”, Bohl C. E. et al.); Bohl C. E. et al. J. MedChem. 54: 3973-3976 (2011); the PDB crystal structure 3B5R (“AndrogenReceptor ligand binding domain in complex with SARM C-31”, Bohl C. E. etal.); Bohl C. E. et al. Bioorg. Med Chem. Lett. 18: 5567-5570 (2008);the PDB crystal structure 2PIP (“Androgen Receptor ligand binding domainin complex with small molecule”, Estebanez-Perpina E. et al.);Estebanez-Perpina. E. Proc. Natl. Acad Sci. 104:16074-16079 (2007); thePDB crystal structure 2PNU (“Androgen Receptor ligand binding domain incomplex with EM5744”, Cantin L. et al.); and, the PDB crystal structure2HVC (“Androgen Receptor ligand binding domain in complex with LGD2226”,Wang F. et al.). For additional related ligands, see, Matias P. M. etal. “Structural Basis for the Glucocorticoid Response in a Mutant HumanAndrogen Receptor (Ar(Ccr)) Derived from an Androgen-IndependentProstate Cancer.” J. Med Chem. 45: 1439 (2002); Sack J. S. et al.“Crystallographic structures of the ligand-binding domains of theandrogen receptor and its T877A mutant complexed with the naturalagonist dihydrotestosterone.” Proc. Natl. Acad Sci. 98: 4904-4909(2001); He B. et al. “Structural basis for androgen receptor interdomainand coactivator interactions suggests a transition in nuclear receptoractivation function dominance.” Mol. Cell 16: 425-438 (2004); Pereira deJesus-Tran K. “Comparison of crystal structures of human androgenreceptor ligand-binding domain complexed with various agonists revealsmolecular determinants responsible for binding affinity.” Protein Sci.15: 987-999 (2006); Bohl C. E. et al. “Structural Basis forAccommodation of Nonsteroidal Ligands in the Androgen Receptor.” MolPharmacol. 63(1):211-23 (2003); Sun C. et al. “Discovery of potentorally-active and muscle-selective androgen receptor modulators based onan N-aryl-hydroxybicyclohydantoin scaffold.” J. Med Chem. 49: 7596-7599(2006); Nirschl A. A. et al. “N-aryl-oxazolidin-2-imine muscle selectiveandrogen receptor modulators enhance potency through pharmacophorereorientation.” J. Med Chem. 52: 2794-2798 (2009); Bohl C. E. et al.“Effect of B-ring substitution pattern on binding mode of propionamideselective androgen receptor modulators.” Bioorg. Med Chem. Lett. 18:5567-5570 (2008); Ullrich T. et al. “3-alkoxy-pyrrolo[1 2-b]pyrazolinesas selective androgen receptor modulators with ideal physicochemicalproperties for transdermal administration.” J. Med Chem. 57: 7396-7411(2014); Saeed A. et al. “2-Chloro-4-[[(1R2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: ATransdermal Selective Androgen Receptor Modulator (SARM) for MuscleAtrophy.” J. Med Chem. 59: 750-755 (2016); Nique et al. “Discovery ofdiarylhydantoins as new selective androgen receptor modulators.” J. MedChem. 55: 8225-8235 (2012); and, Michael E. Jung et al.“Structure-Activity Relationship for Thiohydantoin Androgen ReceptorAntagonists for Castration-Resistant Prostate Cancer (CRPC).” J. MedChem. 53: 2779-2796 (2010).

FIG. 4BB presents examples of Mutant T877A Androgen Receptor TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, the PDB crystal structure40GH (‘Androgen Receptor T877A-AR-LBD”, Hsu C. L. et al.) and the PDBcrystal structure 20Z7 (“Androgen Receptor T877A-AR-LBD”, Bohl C. E. etal.).

FIG. 4CC presents examples of Mutant W741L Androgen Receptor TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, the PDB crystal structure40JB (“Androgen Receptor T877A-AR-LBD”, Hsu C. L. et al.).

FIG. 4DD-4EE presents examples of Estrogen and/or Androgen TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 5A presents examples of Afatinib, a Targeting Ligands for the EGFRand ErbB2/4 receptors. R is the point at which the Linker is attached.

FIG. 5B presents examples of Axitinib, a Targeting Ligands for theVEGFR1/2/3, PDGFRβ, and Kit receptors. R is the point at which theLinker is attached.

FIG. 5C-5D present examples of Bosutinib, a Targeting Ligands for theBCR-Abl, Src, Lyn and Hck receptors. R is the point at which the Linkeris attached.

FIG. 5E presents examples of Cabozantinib, a Targeting Ligands for theRET, c-Met, VEGFR1/2/3, Kit, TrkB, Flt3, Axl, and Tie 2 receptors. R isthe point at which the Linker is attached.

FIG. 5F presents examples of Ceritinib, a Targeting Ligands for the ALK,IGF-1R, InsR, and ROS1 receptors. R is the point at which the Linker isattached.

FIG. 5G presents examples of Crizotinib, a Targeting Ligands for theALK, c-Met, HGFR, ROS1, and MST1R receptors. R is the point at which theLinker is attached.

FIG. 5H presents examples of Dabrafenib, a Targeting Ligands for theB-Raf receptor. R is the point at which the Linker is attached.

FIG. 5I presents examples of Dasatinib, a Targeting Ligands for theBCR-Abl, Src, Lck, Lyn, Yes, Fyn, Kit, EphA2, and PDGFRβ receptors. R isthe point at which the Linker is attached.

FIG. 5J presents examples of Erlotinib, a Targeting Ligands for the EGFRreceptor. R is the point at which the Linker is attached.

FIG. 5K-5M presents examples of Everolimus, a Targeting Ligands for theHER2 breast cancer receptor, the PNET receptor, the RCC receptors, theRAML receptor, and the SEGA receptor. R is the point at which the Linkeris attached.

FIG. 5N presents examples of Gefitinib, a Targeting Ligands for the EGFRand PDGFR receptors. R is the point at which the Linker is attached.

FIG. 5O presents examples of Ibrutinib, a Targeting Ligands for the BTKreceptor. R is the point at which the Linker is attached.

FIG. 5P-5Q present examples of Imatinib, a Targeting Ligands for theBCR-Abl, Kit, and PDGFR receptors. R is the point at which the Linker isattached.

FIG. 5R-5S present examples of Lapatinib, a Targeting Ligands for theEGFR and ErbB2 receptors. R is the point at which the Linker isattached.

FIG. 5T presents examples of Lenvatinib, a Targeting Ligands for theVEGFR1/2/3, FGFR1/2/3/4, PDGFRα, Kit, and RET receptors. R is the pointat which the Linker is attached.

FIG. 5U-5V a present examples of Nilotinib, a Targeting Ligands for theBCR-Abl, PDGRF, and DDR1 receptors. R is the point at which the Linkeris attached.

FIG. 5W-5X present examples of Nintedanib, a Targeting Ligands for theFGFR1/2/3, Flt3, Lck, PDGFRα/β, and VEGFR1/2/3 receptors. R is the pointat which the Linker is attached.

FIG. 5Y-5Z present examples of Palbociclib, a Targeting Ligands for theCDK4/6 receptor. R is the point at which the Linker is attached.

FIG. 5AA presents examples of Pazopanib, a Targeting Ligands for theVEGFR1/2/3, PDGFRα/β, FGFR1/3, Kit, Lck, Fms, and Itk receptors. R isthe point at which the Linker is attached.

FIG. 5BB-5CC present examples of Ponatinib, a Targeting Ligands for theBCR-Abl, T315I VEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET,Tie2, and Flt3 receptors. R is the point at which the Linker isattached.

FIG. 5DD presents examples of Regorafenib, a Targeting Ligands for theVEGFR1/2/3, BCR-Abl, B-Raf, B-Raf (V600E), Kit, PDGFRα/β, RET, FGFR1/2,Tie2, and Eph2A. R is the point at which the Linker is attached.

FIG. 5EE presents examples of Ruxolitinib, a Targeting Ligands for theJAK1/2 receptors. R is the point at which the Linker is attached.

FIG. 5FF-5GG present examples of Sirolimus, a Targeting Ligands for theFKBP12/mTOR receptors. R is the point at which the Linker is attached.

FIG. 5HH presents examples of Sorafenib, a Targeting Ligands for theB-Raf, CDK8, Kit, Flt3, RET, VEGFR1/2/3, and PDGFR receptors. R is thepoint at which the Linker is attached.

FIG. 5II-5JJ present examples of Sunitinib, a Targeting Ligands forPDGFRα/β, VEGFR1/2/3, Kit, Flt3, CSF-1R, RET. R is the point at whichthe Linker is attached.

FIG. 5KK-5LL present examples of Temsirolimus, a Targeting LigandsFKBP12/mTOR. R is the point at which the Linker is attached.

FIG. 5MM presents examples of Tofacitinib, a Targeting Ligands for JAK3receptors. R is the point at which the Linker is attached.

FIG. 5NN presents examples of Trametinib, a Targeting Ligands for theMEK1/2 receptors. R is the point at which the Linker is attached.

FIG. 5OO-5PP presents examples of Vandetanib, a Targeting Ligands forthe EGFR, VEGFR, RET, Tie2, Brk, and EphR. R is the point at which theLinker is attached.

FIG. 5QQ presents examples of Vemurafenib, a Targeting Ligands for theA/B/C-Raf, KSR1, and B-Raf (V600E) receptors. R is the point at whichthe Linker is attached.

FIG. 5RR presents examples of Idelasib, a Targeting Ligands for thePI3Ka receptor. R is the point at which the Linker is attached.

FIG. 5SS presents examples of Buparlisib, a Targeting Ligands for thePI3Ka receptor. R is the point at which the Linker is attached.

FIG. 5TT presents examples of Taselisib, a Targeting Ligands for thePI3Ka receptor. R is the point at which the Linker is attached.

FIG. 5UU presents examples of Copanlisib, a Targeting Ligands for thePI3Ka. R is the point at which the Linker is attached.

FIG. 5VV presents examples of Alpelisib, a Targeting Ligands for thePI3Ka. R is the point at which the Linker is attached.

FIG. 5WW presents examples of Niclosamide, a Targeting Ligands for theCNNTB1. R is the point at which the Linker is attached.

FIG. 6A-6B present examples of the BRD4 Bromodomains of PCAF and GCN5receptors 1 Targeting Ligands wherein R is the point at which the Linkeris attached. For additional examples and related ligands, see, the PDBcrystal structure 5tpx (“Discovery of a PCAF Bromodomain ChemicalProbe”); Moustakim, M., et al. Angew. Chem. Int. Ed. Engl. 56: 827(2017); the PDB crystal structure 5mlj (“Discovery of a Potent, CellPenetrant, and Selective p300/CBP-Associated Factor (PCAF)/GeneralControl Nonderepressible 5 (GCN5) Bromodomain Chemical Probe”); and,Humphreys, P. G. et al. J. Med. Chem. 60: 695 (2017).

FIG. 6C-6D present examples of G9a (EHMT2) Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the PDB crystal structure 3k5k; (“Discovery ofa 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selectiveinhibitor of histone lysine methyltransferase G9a”); Liu, F. et al. J.Med. Chem. 52: 7950 (2009); the PDB crystal structure 3rjw (“A chemicalprobe selectively inhibits G9a and GLP methyltransferase activity incells”); Vedadi, M. et al. Nat. Chem. Biol. 7: 566 (2011); the PDBcrystal structure 4nvq (“Discovery and development of potent andselective inhibitors of histone methyltransferase g9a”); and, Sweis, R.F. et al. ACS Med Chem Lett 5: 205 (2014).

FIG. 6E-6G present examples of EZH2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5ij8 (“Polycombrepressive complex 2 structure with inhibitor reveals a mechanism ofactivation and drug resistance”); Brooun, A. et al. Nat Commun 7: 11384(2016); the PDB crystal structure 5ls6 (“Identification of(R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide(CPI-1205), a Potent and Selective Inhibitor of HistoneMethyltransferase EZH2, Suitable for Phase I Clinical Trials for B-CellLymphomas”); Vaswani, R. G. et al. J. Med. Chem. 59: 9928 (2016); and,the PDB crystal structures 5ij8 and 5ls6.

FIG. 6H-6I present examples of EED Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structures 5hl5 and 5hl9(“Discovery and Molecular Basis of a Diverse Set of Polycomb RepressiveComplex 2 Inhibitors Recognition by EED”); Li, L. et al. PLoS ONE 12:e0169855 (2017); and, the PDB crystal structure 5hl9.

FIG. 6J presents examples of KMT5A (SETD8) Targeting Ligands wherein Ris the point at which the Linker is attached. See for example, the PDBcrystal structure 5t5g.

FIG. 6K-6L present examples of DOT1L Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4eki (“Conformationaladaptation drives potent, selective and durable inhibition of the humanprotein methyltransferase DOTIL”); Basavapathruni, A. et al. Chem. Biol.Drug Des. 80: 971 (2012); the PDB crystal structure 4hra (“Potentinhibition of DOT1L as treatment of MLL-fusion leukemia”); Daigle, S. R.et al. Blood 122: 1017 (2013); the PDB crystal structure 5dry(“Discovery of Novel Dot1L Inhibitors through a Structure-BasedFragmentation Approach”) Chen, C. et al. ACS Med. Chem. Lett. 7: 735(2016); the PDB crystal structure 5dt2 (“Discovery of Novel Dot1LInhibitors through a Structure-Based Fragmentation Approach”); and,Chen, C. et al. ACS Med. Chem. Lett. 7: 735 (2016).

FIG. 6M-6N present examples of PRMT3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 3smq (“An allostericinhibitor of protein arginine methyltransferase 3”); Siarheyeva, A. etal. Structure 20: 1425 (2012); PDB crystal structure 4ryl (“A Potent,Selective and Cell-Active Allosteric Inhibitor of Protein ArginineMethyltransferase 3 (PRMT3)”); and Kaniskan, H. U. et al. Angew. Chem.Int. Ed. Engl. 54: 5166 (2015).

FIG. 6O presents examples of CARM1 (PRMT4) Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the PDB crystal structures 2y1x and 2y1w andrelated ligands described in “Structural Basis for Carm1 Inhibition byIndole and Pyrazole Inhibitors.” Sack, J. S. et al. Biochem. J. 436: 331(2011).

FIG. 6P presents examples of PRMT5 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4×61 and related ligandsdescribed in “A selective inhibitor of PRMT5 with in vivo and in vitropotency in MCL models”. Chan-Penebre, E. Nat. Chem. Biol. 11: 432(2015).

FIG. 6Q presents examples of PRMT6 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4y30 and related ligandsdescribed in “Aryl Pyrazoles as Potent Inhibitors of ArginineMethyltransferases: Identification of the First PRMT6 Tool Compound”.Mitchell, L. H. et al. ACS Med Chem. Lett. 6: 655 (2015).

FIG. 6R presents examples of LSD1 (KDM1A) Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5lgu and related ligandsdescribed in “Thieno[3,2-b]pyrrole-5-carboxamides as New ReversibleInhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2:Structure-Based Drug Design and Structure-Activity Relationship”.Vianello, P. et al. J. Med Chem. 60: 1693 (2017).

FIG. 6S-6T present examples of KDM4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 3rvh; the PDB crystalstructure 5a7p and related ligands described in “Docking and Linking ofFragments to Discover Jumonji Histone Demethylase Inhibitors.”Korczynska, M., et al. J. Med Chem. 59: 1580 (2016); and, the PDBcrystal structure 3f3c and related ligands described in “8-SubstitutedPyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable,KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.”Bavetsias, V. et al. J. Med Chem. 59: 1388 (2016).

FIG. 6U presents examples of KDM5 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 3fun and related ligandsdescribed in “Structural Analysis of Human Kdm5B Guides HistoneDemethylase Inhibitor Development”. Johansson, C. et al. Nat. Chem.Biol. 12: 539 (2016) and the PDB crystal structure 5ceh and relatedligands described in “An inhibitor of KDM5 demethylases reduces survivalof drug-tolerant cancer cells”. Vinogradova, M. et al. Nat. Chem. Biol.12: 531 (2016).

FIG. 6V-6W present examples of KDM6 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4ask and related ligandsdescribed in “A Selective Jumonji H3K27 Demethylase Inhibitor Modulatesthe Proinflammatory Macrophage Response”. Kruidenier, L. et al. Nature488: 404 (2012).

FIG. 6X presents examples of L3MBTL3 targeting ligands wherein R is thepoint at which the Linker is attached. See for example, the PDB crystalstructure 4fl6.

FIG. 6Y presents examples of Menin Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4×5y and related ligandsdescribed in “Pharmacologic Inhibition of the Menin-MLL InteractionBlocks Progression of MLL Leukemia In Vivo” Borkin, D. et al. CancerCell 27: 589 (2015) and the PDB crystal structure 4og8 and relatedligands described in “High-Affinity Small-Molecule Inhibitors of theMenin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a NaturalProtein-Protein Interaction” He, S. et al. J. Med. Chem. 57: 1543(2014).

FIG. 6Z-6AA present examples of HDAC6 Targeting Ligands wherein R is thepoint at which the Linker is attached. See for example, the PDB crystalstructures 5kh3 and 5eei.

FIG. 6BB presents examples of HDAC7 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 3c10 and related ligandsdescribed in “Human HDAC7 harbors a class IIa histonedeacetylase-specific zinc binding motif and cryptic deacetylaseactivity.” Schuetz, A. et al. J. Biol. Chem. 283: 11355 (2008) and thePDB crystal structure PDB 3zns and related ligands described in“Selective Class Iia Histone Deacetylase Inhibition Via a Non-ChelatingZinc Binding Group”. Lobera, M. et al. Nat. Chem. Biol. 9: 319 (2013).

FIG. 7A-7C present examples of Protein Tyrosine Phosphatase,Non-Receptor Type 1, PTP1B Targeting Ligands wherein R is the point atwhich the Linker is attached. For additional examples and relatedligands, see, the PDB crystal structure lbzj described in “Structuralbasis for inhibition of the protein tyrosine phosphatase 1B byphosphotyrosine peptide mimetics” Groves, M. R. et al. Biochemistry 37:17773-17783 (1998); the PDB crystal structure 3cwe described in“Discovery of [(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonicacid, a potent and orally active small molecule PTP1B inhibitor”. Han Y,BioorgMed Chem Lett. 18:3200-5 (2008); the PDB crystal structures 2azrand 2b07 described in “Bicyclic and tricyclic thiophenes as proteintyrosine phosphatase 1B inhibitors.” Moretto, A. F. et al. Bioorg. MedChem. 14: 2162-2177 (2006); the PDB crystal structures PDB 2bgd, 2bge,2cm7, 2cm8, 2cma, 2cmb, 2cmc described in “Structure-Based Design ofProtein Tyrosine Phosphatase-1B Inhibitors”. Black, E. et al. Bioorg.Med Chem. Lett. 15: 2503 (2005) and “Structural Basis for Inhibition ofProtein-Tyrosine Phosphatase 1B by Isothiazolidinone HeterocyclicPhosphonate Mimetics.” Ala, P. J. et al. J. Biol. Chem. 281: 32784(2006); the PDB crystal structures 2f6t and 2f6w described in“1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1Binhibitors”. Klopfenstein, S. R. et al. Bioorg. Med Chem. Lett. 16:1574-1578 (2006); the PDB crystal structures 2h4g, 2h4k, 2hb1 describedin “Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors:Capturing interactions with Asp48.” Wan, Z. K. et al. Bioorg. Med Chem.Lett. 16: 4941-4945 (2006); the PDB crystal structures 2zn7 described in“Structure-based optimization of protein tyrosine phosphatase-1 Binhibitors: capturing interactions with arginine 24”. Wan, Z. K. et al.Chem Med Chem. 3:1525-9 (2008); the PDB crystal structure 2nt7, 2ntadescribed in “Probing acid replacements ofthiophene PTP1B inhibitors.”Wan, Z. K. et al. Bioorg. Med. Chem. Lett. 17: 2913-2920 (2007); and, WO2008148744 A1 assigned to Novartis AG titled “Thiadiazole derivatives asantidiabetic agents”. See also, the PDB crystal structures 1c84, 1c84,1c85, 1c86, 1c88, 118g and described in “2-(oxalylamino)-benzoic acid isa general, competitive inhibitor of protein-tyrosine phosphatases”.Andersen, H. S. et al. J. Biol. Chem. 275: 7101-7108 (2000);“Structure-based design of a low molecular weight, nonphosphorus,nonpeptide, and highly selective inhibitor of protein-tyrosinephosphatase 1B.” Iversen, L. F. et al. J. Biol. Chem. 275: 10300-10307(2000); and, “Steric hindrance as a basis for structure-based design ofselective inhibitors of protein-tyrosine phosphatases”. Iversen, L. F.et al. Biochemistry 40: 14812-14820 (2001).

FIG. 7D presents examples of Tyrosine-protein phosphatase non-receptortype 11, SHP2 Targeting Ligands wherein R is the point at which theLinker is attached. For additional examples and related ligands, see,the crystal structures PDB 4pvg and 305x and described in “Salicylicacid based small molecule inhibitor for the oncogenic Src homology-2domain containing protein tyrosine phosphatase-2 (SHP2).” Zhang, X. etal. J. Med Chem. 53: 2482-2493 (2010); and, the crystal structure PDB5ehr and related ligands described in “Allosteric Inhibition of SHP2:Identification of a Potent, Selective, and Orally EfficaciousPhosphatase Inhibitor.” Garcia Fortanet, J. et al. J. Med Chem. 59:7773-7782 (2016). Also, see the crystal structure PDB 5ehr described in“Allosteric Inhibition of SHP2: Identification of a Potent, Selective,and Orally Efficacious Phosphatase Inhibitor.” Garcia Fortanet, J. etal. J. Med Chem. 59: 7773-7782 (2016) and “Allosteric inhibition of SHP2phosphatase inhibits cancers driven by receptor tyrosine kinases.” Chen,Y. P. et al. Nature 535: 148-152 (2016).

FIG. 7E presents examples of Tyrosine-protein phosphatase non-receptortype 22 Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, the crystalstructure PDB 4j51 described in “A Potent and Selective Small-MoleculeInhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a TargetAssociated with Autoimmune Diseases.” He, Y. et al. J. Med Chem. 56:4990-5008 (2013).

FIG. 7F presents examples of Scavenger mRNA-decapping enzyme DcpSTargeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, the crystalstructures PDB 3b17, 3b19, 3bla, 4qde, 4qdv, 4qeb and related ligandsdescribed in “DcpS as a therapeutic target for spinal muscular atrophy.”Singh, J. et al. ACS Chem.Biol. 3: 711-722 (2008).

FIG. 8A-8S present examples of BRD4 Bromodomain 1 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structures PDB 3u5k and3u51 and related ligands in Filippakopoulos, P. et al. “Benzodiazepinesand benzotriazepines as protein interaction inhibitors targetingbromodomains of the BET family”, Bioorg. Med. Chem. 20: 1878-1886(2012); the crystal structure PDB 3u51; the crystal structure PDB 3zyuand related ligands described in Dawson, M. A. et al. “Inhibition of BetRecruitment to Chromatin as an Effective Treatment for Mll-FusionLeukaemia.” Nature 478: 529 (2011); the crystal structure PDB 4bwl andrelated ligands described in Mirguet, O. et al. “Naphthyridines as NovelBet Family Bromodomain Inhibitors.” Chemmedchem 9: 589 (2014); thecrystal structure PDB 4cfl and related ligands described in Dittmann, A.et al. “The Commonly Used Pi3-Kinase Probe Ly294002 is an Inhibitor ofBet Bromodomains” ACS Chem. Biol. 9: 495 (2014); the crystal structurePDB 4e96 and related ligands described in Fish, P. V. et al.“Identification of a chemical probe for bromo and extra C-terminalbromodomain inhibition through optimization of a fragment-derived hit.”J. Med. Chem. 55: 9831-9837 (2012); the crystal structure PDB 4clb andrelated ligands described in Atkinson, S. J. et al. “The Structure BasedDesign of Dual Hdac/Bet Inhibitors as Novel Epigenetic Probes.”Medchemcomm 5: 342 (2014); the crystal structure PDB 4f3i and relatedligands described in Zhang, G. et al. “Down-regulation of NF-{kappa}BTranscriptional Activity in HIV-associated Kidney Disease by BRD4Inhibition.” J. Biol. Chem. 287: 28840-28851 (2012); the crystalstructure PDB 4hxl and related ligands described in Zhao, L.“Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of theHistone Reader BRD4 Bromodomain.” J. Med Chem. 56: 3833-3851 (2013); thecrystal structure PDB 4hxs and related ligands described in Zhao, L. etal. “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors ofthe Histone Reader BRD4 Bromodomain.” J. Med Chem. 56: 3833-3851 (2013);the crystal structure PDB 41rg and related ligands described in Gehling,V. S. et al. “Discovery, Design, and Optimization of Isoxazole AzepineBET Inhibitors.” ACS Med Chem Lett 4: 835-840 (2013); the crystalstructure PDB 4mep and related ligands described in Vidler, L. R.“Discovery of Novel Small-Molecule Inhibitors of BRD4 UsingStructure-Based Virtual Screening.” et al. J. Med Chem. 56: 8073-8088(2013); the crystal structures PDB 4nr8 and PDB 4c77 and related ligandsdescribed in Ember, S. W. et al. “Acetyl-lysine Binding Site ofBromodomain-Containing Protein 4 (BRD4) Interacts with Diverse KinaseInhibitors”. ACS Chem.Biol. 9: 1160-1171 (2014); the crystal structurePDB 4o7a and related ligands described in Ember, S. W. et al.“Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4)Interacts with Diverse Kinase Inhibitors.” ACS Chem. Biol. 9: 1160-1171(2014); the crystal structure PDB 407b and related ligands described in“Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4)Interacts with Diverse Kinase Inhibitors.” Ember, S. W. et al. (2014)ACS Chem. Biol. 9: 1160-1171; the crystal structure PDB 4o7c and relatedligands described in Ember, S. W. et al. “Acetyl-lysine Binding Site ofBromodomain-Containing Protein 4 (BRD4) Interacts with Diverse KinaseInhibitors”. ACS Chem. Biol. 9: 1160-1171 (2014); the crystal structurePDB 4gpj; the crystal structure PDB 4uix and related ligands describedin Theodoulou, N. H. et al. “The Discovery of I-Brd9, a Selective CellActive Chemical Probe for Bromodomain Containing Protein 9 Inhibition”.J. Med Chem. 59: 1425 (2016); the crystal structure PDB 4uiz and relatedligands described in Theodoulou, N. H., et al. “The Discovery of I-Brd9,a Selective Cell Active Chemical Probe for Bromodomain ContainingProtein 9 Inhibition”. J. Med Chem. 59: 1425 (2016); the crystalstructure PDB 4wiv and related ligands described in McKeown, M. R. etal. “Biased multicomponent reactions to develop novel bromodomaininhibitors.” J. Med Chem. 57: 9019-9027 (2014); the crystal structurePDB 4×2i and related ligands described in Taylor, A. M. et al.“Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally ActiveInhibitors of BET Bromodomains.” ACS Med Chem. Lett. 7: 145-150 (2016);the crystal structure PDB 4yh3; And related ligands described in Duffy,B. C. “Discovery of a new chemical series of BRD4(1) inhibitors usingprotein-ligand docking and structure-guided design.” Bioorg. Med Chem.Lett. 25: 2818-2823 (2015); the crystal structure PDB 4yh4 and relatedligands described in Duffy, B. C. “Discovery of a new chemical series ofBRD4(1) inhibitors using protein-ligand docking and structure-guideddesign.” Bioorg. Med Chem. Lett. 25: 2818-2823 (2015); the crystalstructure PDB 4zlq and related ligands described in Taylor, A. M.“Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally ActiveInhibitors of BET Bromodomains.” ACS Med Chem. Lett. 7: 145-150 (2016);the crystal structure PDB 4zwl; the crystal structure PDB 5a5s andrelated ligands described in Demont, E. H. “Fragment-Based Discovery ofLow-Micromolar Atad2 Bromodomain Inhibitors. J. Med Chem. 58: 5649(2015); the crystal structure PDB 5a85 and related ligands described inBamborough, P. “Structure-Based Optimization of Naphthyridones IntoPotent Atad2 Bromodomain Inhibitors” J. Med Chem. 58: 6151 (2015); thecrystal structure PDB 5acy and related ligands described in Sullivan, J.M. “Autism-Like Syndrome is Induced by Pharmacological Suppression ofBet Proteins in Young Mice.” J. Exp. Med 212: 1771 (2015); the crystalstructure PDB 5ad2 and related ligands described in Waring, M. J. et al.“Potent and Selective Bivalent Inhibitors of Bet Bromodomains”. Nat.Chem. Biol. 12: 1097 (2016); the crystal structure PDB 5cfw and relatedligands described in Chekler, E. L. et al. “Transcriptional Profiling ofa Selective CREB Binding Protein Bromodomain Inhibitor HighlightsTherapeutic Opportunities.” Chem. Biol. 22: 1588-1596 (2015); thecrystal structure PDB 5cqt and related ligands described in Xue, X. etal. “Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BETBromodomain Inhibitors: Structure-Based Virtual Screening, Optimization,and Biological Evaluation”. J. Med Chem. 59: 1565-1579 (2016); thecrystal structure PDB 5d3r and related ligands described in Hugle, M. etal. “4-Acyl Pyrrole Derivatives Yield Novel Vectors for DesigningInhibitors of the Acetyl-Lysine Recognition Site of BRD4(1)”. J. MedChem. 59: 1518-1530 (2016); the crystal structure PDB 5dlx and relatedligands described in Milhas, S. et al. “Protein-Protein InteractionInhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.”(2016) ACS Chem.Biol. 11: 2140-2148; the crystal structure PDB 5dlz andrelated ligands described in Milhas, S. et al. “Protein-ProteinInteraction Inhibition (2P21)-Oriented Chemical Library Accelerates HitDiscovery.” ACS Chem. Biol. 11: 2140-2148 (2016); the crystal structurePDB 5dw2 and related ligands described in Kharenko, O. A. et al.“RVX-297-a novel BD2 selective inhibitor of BET bromodomains.” Biochem.Biophys. Res. Commun. 477: 62-67 (2016); the crystal structure PDB 5dlx;the crystal structure PDB 5his and related ligands described inAlbrecht, B. K. et al. “Identification of a BenzoisoxazoloazepineInhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Familyas a Candidate for Human Clinical Trials.” J. Med Chem. 59: 1330-1339(2016); the crystal structure PDB 5ku3 and related ligands described inCrawford, T. D. et al. “Discovery of a Potent and Selective in VivoProbe (GNE-272) for the Bromodomains of CBP/EP300”. J. Med Chem. 59:10549-10563 (2016); the crystal structure PDB 51j2 and related ligandsdescribed in Bamborough, P. et al. “A Chemical Probe for the ATAD2Bromodomain.” Angew. Chem. Int. Ed Engl. 55: 11382-11386 (2016); thecrystal structure PDB 5dlx and related ligands described in Wang, L.“Fragment-based, structure-enabled discovery of novel pyridones andpyridone macrocycles as potent bromodomain and extra-terminal domain(BET) family bromodomain inhibitors”. J. Med Chem.10.1021/acs.jmedchem.7b00017 (2017); WO 2015169962 A1 titled“Benzimidazole derivatives as BRD4 inhibitors and their preparation anduse for the treatment of cancer” assigned to Boehringer IngelheimInternational GmbH, Germany; and, WO 2011143669 A2 titled“Azolodiazepine derivatives and their preparation, compositions andmethods for treating neoplasia, inflammatory disease and otherdisorders” assigned to Dana-Farber Cancer Institute, Inc, USA.

FIG. 8T-8V present examples of ALK Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 2xb7 and 2xba andrelated ligands described in Bossi, R. T. et al. “Crystal Structures ofAnaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors”Biochemistry 49: 6813-6825 (2010); the crystal structures PDB 2yfx,4ccb, 4ccu, amd 4cd0 snd related ligands described in Huang, Q. et al.“Design of Potent and Selective Inhibitors to Overcome ClinicalAnaplastic Lymphoma Kinase Mutations Resistant to Crizotinib.” J. MedChem. 57: 1170 (2014); the crystal structures PDB, 4cli, 4cmo, and 4cnhand related ligands described in Johnson, T. W. et al. “Discovery of(10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile(Pf-06463922), a Macrocyclic Inhibitor of Alk/Ros1 with Pre-ClinicalBrain Exposure and Broad Spectrum Potency Against Alk-ResistantMutations.” J. Med Chem. 57: 4720 (2014); the crystal structure PDB 4fnyand related ligands described in Epstein, L. F. et al. “The R1275QNeuroblastoma Mutant and Certain ATP-competitive Inhibitors StabilizeAlternative Activation Loop Conformations of Anaplastic LymphomaKinase.” J. Biol. Chem. 287: 37447-37457 (2012). the crystal structurePDB 4dce and related ligands described in Bryan, M. C. et al “Rapiddevelopment of piperidine carboxamides as potent and selectiveanaplastic lymphoma kinase inhibitors.” J. Med Chem. 55: 1698-1705(2012); the crystal structure PDB 4joa and related ligands described inGummadi, V. R. et al. “Discovery of 7-azaindole based anaplasticlymphoma kinase (ALK) inhibitors: wild type and mutant (L1 196M) activecompounds with unique binding mode.” (2013) Bioorg. Med Chem. Lett. 23:4911-4918; and, the crystal structure PDB 5iui and related ligandsdescribed in Tu, C. H. et al. “Pyrazolylamine Derivatives Reveal theConformational Switching between Type I and Type II Binding Modes ofAnaplastic Lymphoma Kinase (ALK).” J. Med Chem. 59: 3906-3919 (2016).

FIG. 8W-8X present examples of BTK Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3gen, 3piz and relatedligands described in Marcotte, D. J. et al. “Structures of humanBruton's tyrosine kinase in active and inactive conformations suggest amechanism of activation for TEC family kinases.” Protein Sci. 19:429-439 (2010) and Kuglstatter, A. et al. “Insights into theconformational flexibility of Bruton's tyrosine kinase from multipleligand complex structures” Protein Sci. 20: 428-436” (2011); the crystalstructure PDB 3ocs, 4ot6 and related ligands described in Lou, Y. et al.“Structure-Based Drug Design of RN486, a Potent and Selective Bruton'sTyrosine Kinase (BTK) Inhibitor, for the Treatment of RheumatoidArthritis” J. Med Chem. 58: 512-516 (2015); the crystal structures PDB5fbn and 5fbo and related ligands described in Liu, J. et al. “Discoveryof 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for theTreatment of Rheumatoid Arthritis.” ACS Med Chem. Lett. 7: 198-203(2016); the crystal structure PDB 3pix and related ligands described inKuglstatter, A. et al. “Insights into the conformational flexibility ofBruton's tyrosine kinase from multiple ligand complex structures.”Protein Sci. 20: 428-436 (2011); and, the crystal structure PDB 3pij andrelated ligands described in Bujacz, A. et al. “Crystal structures ofthe apo form of beta-fructofuranosidase from Bifidobacterium longum andits complex with fructose.” Febs J. 278: 1728-1744 (2011).

FIG. 8Y presents examples of FLT3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 4xuf and 4rt7 andrelated ligands described in Zorn, J. A. et al. “Crystal Structure ofthe FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)”. PlosOne 10: e0121177-e0121177 (2015).

FIG. 8Z-8AA present examples of TNIK Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 2×7f; the crystalstructures PDB 5ax9 and 5d7a; and, related ligands described in Masuda,M. et al. “TNIK inhibition abrogates colorectal cancer stemness.” NatCommun 7: 12586-12586 (2016).

FIG. 8BB-8CC present examples of NTRK1, NTRK2, and NTRK3 TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, the crystal structure PDB4aoj and related ligands described in Wang, T. et al. “Discovery ofDisubstituted Imidazo[4,5-B]Pyridines and Purines as Potent TrkaInhibitors.” ACS Med Chem. Lett. 3: 705 (2012); the crystal structuresPDB 4pmm, 4pmp, 4pms and 4pmt and related ligands described in Stachel,S. J. et al. “Maximizing diversity from a kinase screen: identificationof novel and selective pan-Trk inhibitors for chronic pain.” J. MedChem. 57: 5800-5816 (2014); the crystal structures PDB 4yps and 4yne sndrelated ligands described in Choi, H. S. et al. “(R)-2-PhenylpyrrolidineSubstituted Imidazopyridazines: A New Class of Potent and SelectivePan-TRK Inhibitors.” ACS Med Chem. Lett. 6: 562-567 (2015); the crystalstructures PDB 4at5 and 4at3 and related ligands described in Bertrand,T. et al. “The Crystal Structures of Trka and Trkb Suggest Key Regionsfor Achieving Selective Inhibition.” J. Mol. Biol. 423: 439 (2012); and,the crystal structures PDB 3v5q and 4ymj and related ligands describedin Albaugh, P. et al. “Discovery of GNF-5837, a selective TRK Inhibitorwith efficacy in rodent cancer tumor models.” ACS Med Chem. Lett. 3:140-145 (2012) and Choi, H. S. et al. “(R)-2-PhenylpyrrolidineSubstitute Imidazopyridazines: a New Class of Potent and SelectivePan-TRK Inhibitors.” ACS Med Chem Lett 6: 562-567 (2015).

FIG. 8DD-8EE present examples of FGFR1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 3tto and 2fgi andrelated ligands described in Brison, Y. et al. “Functional andstructural characterization of alpha-(1-2) branching sucrase derivedfrom DSR-E glucansucrase.” J. Biol. Chem. 287: 7915-7924 (2012) andMohammadi, M. et al. “Crystal structure of an angiogenesis inhibitorbound to the FGF receptor tyrosine kinase domain.” EMBO J. 17: 5896-5904(1998); the crystal structure PDB 4fb3; the crystal structure PDB 4rwkand related ligands described in Harrison, C. et al. “Polyomavirus largeT antigen binds symmetrical repeats at the viral origin in anasymmetrical manner.” J. Virol. 87: 13751-13759 (2013); the crystalstructure PDB 4rwl and related ligands described in Sohl, C. D. et al.“Illuminating the Molecular Mechanisms of Tyrosine Kinase InhibitorResistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel ofTargeted Therapy.” ACS Chem. Biol. 10: 1319-1329 (2015); the crystalstructure PDB 4uwc; the crystal structure PDB 4v01 and related ligandsdescribed in Tucker, J. A. et al. “Structural Insights Into Fgfr KinaseIsoform Selectivity: Diverse Binding Modes of Azd4547 and Ponatinib inComplex with Fgfr1 and Fgfr4.” Structure 22: 1764 (2014).; the crystalstructure PDB 5a46 and related ligands described in Klein, T. et al.“Structural and Dynamic Insights Into the Energetics of Activation LoopRearrangement in Fgfrl Kinase.” Nat. Commun. 6: 7877 (2015); and, thecrystal structure PDB 5ew8 and related ligands described in Patani, H.et al. “Landscape of activating cancer mutations in FGFR kinases andtheir differential responses to inhibitors in clinical use.” Oncotarget7: 24252-24268 (2016).

FIG. 8FF presents examples of FGFR2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 2pvf and related ligandsdescribed in Chen, H. et al. “A molecular brake in the kinase hingeregion regulates the activity of receptor tyrosine kinases.” Mol. Cell27: 717-730 (2007).

FIG. 8GG presents examples of FGFR4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 4tyi and related ligandsdescribed in Lesca, E. et al. “Structural analysis of the humanfibroblast growth factor receptor 4 kinase.” J. Mol. Biol. 426:3744-3756 (2014).

FIG. 8HH-8II present examples of MET Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 3qti and 3zcl; thecrystal structures PDB 4xmo, 4xyf, and 3zcl and related ligandsdescribed in Peterson, E. A. et al. “Discovery of Potent and Selective8-Fluorotriazolopyridine c-Met Inhibitors.” J. Med. Chem. 58: 2417-2430(2015) and Cui, J. J. et al. “Lessons from(S)-6-(1-(6-(1-Methyl-1H-Pyrazol-4-Yl)-[1,2,4]Triazolo[4,3-B]Pyridazin-3-Yl)Ethyl)Quinoline (Pf-04254644), anInhibitor of Receptor Tyrosine Kinase C-met with High Protein KinaseSelectivity But Broad Phosphodiesterase Family Inhibition Leading toMyocardial Degeneration in Rats.” J. Med. Chem. 56: 6651 (2013); thecrystal structure PDB 5eyd and related ligands described in Boezio, A.A. et al. “Discovery of(R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one(AMG 337), a Potent and Selective Inhibitor of MET with High UnboundTarget Coverage and Robust In Vivo Antitumor Activity.” J. Med Chem. 59:2328-2342 (2016); the crystal structure PDB 3ce3 and related ligandsdescribed in Kim, K. S. et al. “Discovery of pyrrolopyridine-pyridonebased inhibitors of Met kinase: synthesis, X-ray crystallographicanalysis, and biological activities.” J. Med Chem. 51: 5330-5341 (2008);the crystal structure PDB 2rfn and related ligands described in Bellon,S. F. et al. “c-Met inhibitors with novel binding mode show activityagainst several hereditary papillary renal cell carcinoma-relatedmutations.” J. Biol. Chem. 283: 2675-2683 (2008); and, the crystalstructure PDB 5dg5 and related ligands described in Smith, B. D. et al“Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, andMicroenvironment-Mediated Drug Resistance via Balanced Inhibition ofMET, TIE2, and VEGFR2.”. Mol. Cancer Ther. 14: 2023-2034 (2015).

FIG. 8JJ presents examples of JAK1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 4ivd and related ligandsdescribed in Zak, M. et al. “Identification of C-2 HydroxyethylImidazopyrrolopyridines as Potent JAK1 Inhibitors with FavorablePhysicochemical Properties and High Selectivity over JAK2.” J. Med Chem.56: 4764-4785 (2013); the crystal structure PDB 5ele and related ligandsdescribed in Vasbinder, M. M. et al. “Identification ofazabenzimidazoles as potent JAK1 selective inhibitors.” Bioorg. MedChem. Lett. 26: 60-67 (2016); the crystal structure PDB 5hx8 and relatedligands described in Simov, V., et al. “Structure-based design anddevelopment of (benz)imidazole pyridones as JAK1-selective kinaseinhibitors.” Bioorg. Med Chem. Lett. 26: 1803-1808 (2016); the crystalstructure PDB 5hx8 and related ligands described in Caspers, N. L. etal. “Development of a high-throughput crystal structure-determinationplatform for JAK1 using a novel metal-chelator soaking system”. ActaCrystallogr. Sect. F 72: 840-845 (2016); and, Kettle, J. G. “Discoveryof the JAK1 selective kinase inhibitor AZD4205”, AACR National Meeting,April 2017.

FIG. 8KK-8LL present examples of JAK2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3ugc and related ligandsdescribed in Andraos, R. et al. “Modulation of activation-loopphosphorylation by JAK inhibitors is binding mode dependent.” CancerDiscov 2: 512-523 (2012); the crystal structures PDB 5cf4, 5cf5, 5cf6and 5cf8 and related ligands described in Hart, A. C. et al.“Structure-Based Design of Selective Janus Kinase 2Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors.” ACS Med Chem. Lett. 6:845-849 (2015); the crystal structure PDB 5aep and related ligandsdescribed in Brasca, M. G. et al “Novel Pyrrole Carboxamide Inhibitorsof Jak2 as Potential Treatment of Myeloproliferative Disorders” Bioorg.Med Chem. 23: 2387 (2015); the crystal structures PDB 4ytf, 4yth and4yti and related ligands described in Farmer, L. J. et al. “Discovery ofVX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitorfor the Treatment of Autoimmune Diseases.” J. Med Chem. 58: 7195-7216(2015); the crystal structure PDB 4ytf, 4yth, 4yti and related ligandsdescribed in Menet, C. J. et al. “Triazolopyridines as Selective JAK1Inhibitors: From Hit Identification to GLPG0634.” J. Med Chem. 57:9323-9342 (2014); the crystal structure PDB 4ji9 and related ligandsdescribed in Siu, M. et al. “2-Amino-[1,2,4]triazolo[1,5-a]pyridines asJAK2 inhibitors.” Bioorg. Med Chem. Lett. 23: 5014-5021 (2013); and, thecrystal structures PDB 3io7 and3iok and related ligands described inSchenkel, L. B. et al. “Discovery of potent and highly selectivethienopyridine janus kinase 2 inhibitors.” J. Med. Chem. 54: 8440-8450(2011).

FIG. 8MM presents examples of JAK3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3zc6 and related ligandsdescribed in Lynch, S. M. et al. “Strategic Use of Conformational Biasand Structure Based Design to Identify Potent Jak3 Inhibitors withImproved Selectivity Against the Jak Family and the Kinome.” Bioorg. MedChem. Lett. 23: 2793 (2013); and, the crystal structures PDB 4hvd, 4i6q,and 3zep and related ligands described in Soth, M. et al. “3-AmidoPyrrolopyrazine JAK Kinase Inhibitors: Development of a JAK3 vs JAK1Selective Inhibitor and Evaluation in Cellular and in Vivo Models.” J.Med Chem. 56: 345-356 (2013) and Jaime-Figueroa, S. et al. “Discovery ofa series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potentJAK3 kinase inhibitors.” Bioorg. Med Chem. Lett. 23: 2522-2526 (2013).

FIG. 8NN-8OO present examples of KIT Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 1t46 and related ligandsdescribed in Mol, C. D. et al. “Structural basis for the autoinhibitionand STI-571 inhibition of c-Kit tyrosine kinase.” J. Biol. Chem. 279:31655-31663 (2004); and, the crystal structure PDB 4uOi and relatedligands described in Garner, A. P. et al. “Ponatinib Inhibits PolyclonalDrug-Resistant KIT Oncoproteins and Shows Therapeutic Potential inHeavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients.”Clin. Cancer Res. 20: 5745-5755 (2014).

FIG. 8PP-8VV present examples of EGFR Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 5hcy, 4rj4, and 5cav;Heald, R., “Noncovalent Mutant Selective Epidermal Growth FactorReceptor Inhibitors: A Lead Optimization Case Study”, J. Med Chem. 58,8877-8895 (2015); Hanano, E. J., “Discovery of Selective and NoncovalentDiaminopyrimidine-Based Inhibitors of Epidermal Growth Factor ReceptorContaining the T790M Resistance Mutation. “J. Med Chem., 57, 10176-10191(2014); Chan, B. K. et al. “Discovery of a Noncovalent, Mutant-SelectiveEpidermal Growth Factor Receptor Inhibitor” J. Med Chem. 59, 9080(2016); the crystal structure PDB 5d41 and related ligands described inJia, Y. et al., “Overcoming EGFR(T790M) and EGFR(C797S) resistance withmutant-selective allosteric inhibitors” Nature 534, 129 (2016); Ward, R.A. “Structure- and reactivity-based development of covalent inhibitorsof the activating and gatekeeper mutant forms of the epidermal growthfactor receptor (EGFR)” J. Med Chem. 56, 7025-7048 (2013); the crystalstructure PDB 4zau and related ligands described in “Discovery of aPotent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing andT790M Resistance Mutations That Spares the Wild Type Form of theReceptor” J. Med Chem., 57 (20), 8249-8267 (2014); the crystal structurePDB 5em7 and related ligands described in Bryan, M. C. et al. “Pyridonesas Highly Selective, Noncovalent Inhibitors of T790M Double Mutants ofEGFR “ACS Med Chem. Lett., 7 (1), 100-104 (2016); the crystal structurePDB 3IKA and related ligands described in Zhou, W. et al. “Novelmutant-selective EGFR kinase inhibitors against EGFR T790M” Nature462(7276), 1070-1074 (2009); the crystal structure see PDB 5feq andrelated ligands described in Lelais, G., J. “Discovery of(R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor ofOncogenic (L858R, exl9del) and Resistant (T790M) EGFR Mutants for theTreatment of EGFR Mutant Non-Small-Cell Lung Cancers” Med Chem., 59(14), 6671-6689 (2016); Lee, H.-J. “Noncovalent Wild-type-SparingInhibitors of EGFR T790M” Cancer Discov. 3(2): 168-181 (2013); thecrystal structure PDB 5j7h and related ligands described in Huang, W-S.et al. “Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing,Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.” J. MedChem. 59: 4948-4964 (2016); the crystal structure PDB 4v0g and relatedligands described in Hennessy, E. J. et al. “Utilization ofStructure-Based Design to Identify Novel, Irreversible Inhibitors ofEGFR Harboring the T790M Mutation.” ACS. Med Chem. Lett. 7: 514-519(2016); the crystal structure PDB 5hg7 and related ligands described inCheng, H. “Discovery of1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one(PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor ofT790M-Containing EGFR Mutants.” J. Med Chem. 59: 2005-2024 (2016); Hao,Y. “Discovery and Structural Optimization of N5-Substituted6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal GrowthFactor Receptor (EGFR) Inhibitors against L858R/T790M ResistanceMutation.” J. Med Chem. 59: 7111-7124 (2016); the crystal structure PDB5ug8, 5ug9, and 5ugc and related ligands described in Planken, S.“Discovery ofN-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide(PF-06747775) through Structure-Based Drug Design: A High AffinityIrreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivityover Wild-Type EGFR.” J. Med Chem. 60: 3002-3019 (2017); the crystalstructure PDB 5gnk and related ligands described in Wang, A. “Discoveryof(R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitorwith a Distinct Binding Mode.” J. Med Chem. 60: 2944-2962 (2017); and,Juchum, M. “Trisubstituted imidazoles with a rigidized hinge bindingmotif act as single digit nM inhibitors of clinically relevant EGFRL858R/T790M and L858R/T790M/C797S mutants: An example of targethopping.” J. Med Chem. DOI: 10.1021/acs.jmedchem.7b00178 (2017).

FIG. 8WW-8XX present examples of PAK1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Rudolph, J. et al. “Chemically Diverse Group Ip21-Activated Kinase (PAK) Inhibitors Impart Acute CardiovascularToxicity with a Narrow Therapeutic Window.” J. Med Chem. 59, 5520-5541(2016) and Karpov A S, et al. ACS Med Chem Lett. 22; 6(7):776-81 (2015).

FIG. 8YY presents examples of PAK4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Staben S T, et al. J Med Chem. 13; 57(3):1033-45(2014) and Guo, C. et al. “Discovery of pyrroloaminopyrazoles as novelPAK inhibitors” J. Med Chem. 55, 4728-4739 (2012).

FIG. 8ZZ-8AAA present examples of IDO Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Yue, E. W.; et al. “Discovery of potentcompetitive inhibitors of indoleamine 2,3-dioxygenase with in vivopharmacodynamic activity and efficacy in a mouse melanoma model.” J. MedChem. 52, 7364-7367 (2009); Tojo, S.; et al. “Crystal structures andstructure, and activity relationships of imidazothiazole derivatives asIDO1 inhibitors.” ACS Med Chem. Lett. 5, 1119-1123 (2014); Mautino, M.R. et al. “NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathwayinhibitor drug candidate for cancer therapy” Abstract 491, AACR 104thAnnual Meeting 2013; Apr. 6-10, 2013; Washington, D.C.; and,WO2012142237 titled “Fused imidazole derivatives useful as IDOinhibitors”.

FIG. 8BBB-8EEE present examples of ERK1 and ERK2 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structures PDB 5K4I and5K4J and related ligands described in Blake, J. F. et al. “Discovery of(S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2)Inhibitor in Early Clinical Development” J. Med Chem. 59: 5650-5660(2016); the crystal structure PDB 5BVF and related ligands described inBagdanoff, J. T. et al. “Tetrahydropyrrolo-diazepenones as inhibitors ofERK2 kinase” Bioorg. Med Chem. Lett. 25, 3788-3792 (2015); the crystalstructure PDB 4QYY and related ligands described in Deng, Y. et al.“Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity SelectionScreening of an Inactive Kinase” J. Med Chem. 57: 8817-8826 (2014); thecrystal structures PDB 5HD4 and 5HD7 and the related ligands describedin Jha, S. et al. “Dissecting Therapeutic Resistance to ERK Inhibition”Mol.Cancer Ther. 15: 548-559 (2016); the crystal structure PDB 4XJO andrelated ligands described in Ren, L. et al. “Discovery of highly potent,selective, and efficacious small molecule inhibitors of ERK1/2.” J. MedChem. 58: 1976-1991 (2015); the crystal structures PDB 4ZZM, 4ZZN, 4ZZOand related ligands described in Ward, R. A. et al. “Structure-GuidedDesign of Highly Selective and Potent Covalent Inhibitors of Erk1/2.” J.Med Chem. 58: 4790 (2015); Burrows, F. et al. “KO-947, a potent ERKinhibitor with robust preclinical single agent activity in MAPK pathwaydysregulated tumors” Poster #5168, AACR National Meeting 2017; Bhagwat,S. V. et al. “Discovery of LY3214996, a selective and novel ERK1/2inhibitor with potent antitumor activities in cancer models with MAPKpathway alterations.” AACR National Meeting 2017; the crystal structuresPDB 3FHR and 3FXH and related ligands described in Cheng, R. et al.“High-resolution crystal structure of human Mapkap kinase 3 in complexwith a high affinity ligand” Protein Sci. 19: 168-173 (2010); thecrystal structures PDB 5NGU, 5NHF, 5NHH, 5NHJ, 5NHL, 5NHO, 5NHP, and5NHV and related ligands described in Ward, R. A. et al.“Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2from a Modestly Active and Promiscuous Chemical Start Point.” J. Med.Chem. 60, 3438-3450 (2017); and, the crystal structures PDB 3 SHE and3R1N and related ligands described in Oubrie, A. et al. “Novel ATPcompetitive MK2 inhibitors with potent biochemical and cell-basedactivity throughout the series.” Bioorg. Med. Chem. Lett. 22: 613-618(2012).

FIG. 8FFF-8III present examples of ABL1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 1fpu and 2e2b andrelated ligands described in Schindler, T., et al. “Structural mechanismfor STI-571 inhibition of abelson tyrosine kinase”, Science 289:1938-1942 (2000); and Horio, T. et al. “Structural factors contributingto the Abl/Lyn dual inhibitory activity of 3-substituted benzamidederivatives”, Bioorg. Med. Chem. Lett. 17: 2712-2717 (2007); the crystalstructures PDB 2hzn and 2hiw and related ligands described inCowan-Jacob, S. W. et al. “Structural biology contributions to thediscovery of drugs to treat chronic myelogenous leukaemia”, ActaCrystallog. Sect. D 63: 80-93 (2007) and Okram, B. et al. “A generalstrategy for creating”, Chem. Biol. 13: 779-786 (2006); the crystalstructure PDB 3cs9 and related ligands described in Weisberg, E. et al.“Characterization of AMN107, a selective inhibitor of native and mutantBcr-Abl”, Cancer Cell 7: 129-14 (2005); the crystal structure PDB 3ik3and related ligands described in O'Hare, T. et al. “AP24534, apan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibitsthe T315I mutant and overcomes mutation-based resistance”, Cancer Cell16: 401-412 (2009); the crystal structure PDB 3mss and related ligandsdescribed in Jahnke, W. et al. “Binding or bending: distinction ofallosteric Abl kinase agonists from antagonists by an NMR-basedconformational assay”, J. Am. Chem. Soc. 132: 7043-7048 (2010); thecrystal structure PDB 3oy3 and related ligands described in Zhou, T. etal. “Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib(AP24534): Lessons for Overcoming Kinase Inhibitor Resistance”, Chem.Biol. Drug Des. 77: 1-11 (2011); the crystal structures PDB 3qri and3qrk and related ligands described in Chan, W. W. et al. “ConformationalControl Inhibition of the BCR-ABL1 Tyrosine Kinase, Including theGatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036”,Cancer Cell 19: 556-568 (2011); the crystal structure PDB 5hu9 and 2f4jand related ligands described in Liu, F. et al. “Discovery andcharacterization of a novel potent type II native and mutant BCR-ABLinhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)”, Oncotarget 7:45562-45574 (2016) and Young, M. A. et al. “Structure of the kinasedomain of an imatinib-resistant Abl mutant in complex with the Aurorakinase inhibitor VX-680”, Cancer Res. 66: 1007-1014 (2006); the crystalstructure PDB 2gqg and 2qoh and related ligands described in Tokarski,J. S. et al. “The Structure of Dasatinib (BMS-354825) Bound to ActivatedABL Kinase Domain Elucidates Its Inhibitory Activity againstImatinib-Resistant ABL Mutants”, Cancer Res. 66: 5790-5797 (2006); andZhou, T. et al. “Crystal Structure of the T315I Mutant of Abl Kinase”,Chem. Biol. Drug Des. 70: 171-181 (2007); the crystal structure PDB 2gqgand 2qoh and related ligands described in Tokarski, J. S. et al. “TheStructure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase DomainElucidates Its Inhibitory Activity against Imatinib-Resistant ABLMutants”, Cancer Res. 66: 5790-5797 (2006) and Zhou, T. et al. “CrystalStructure of the T315I Mutant of Abl Kinase”, Chem. Biol. Drug Des. 70:171-181 (2007); the crystal structure PDB 2gqg and 2qoh and relatedligands described in Tokarski, J. S. et al. “The Structure of Dasatinib(BMS-354825) Bound to Activated ABL Kinase Domain Elucidates ItsInhibitory Activity against Imatinib-Resistant ABL Mutants”, Cancer Res.66: 5790-5797 (2006) and Zhou, T. et al. “Crystal Structure of the T315IMutant of Abl Kinase”, Chem. Biol. Drug Des. 70: 171-181(2007); thecrystal structures PDB 3dk3 and 3dk8 and related ligands described inBerkholz, D. S. et al. “Catalytic cycle of human glutathione reductasenear 1 A resolution” J. Mol. Biol. 382: 371-384 (2008); the crystalstructure PDB 3ue4 and related ligands described in Levinson, N. M. etal. “Structural and spectroscopic analysis of the kinase inhibitorbosutinib and an isomer of bosutinib binding to the abl tyrosine kinasedomain”, Plos One 7: e29828-e29828 (2012); the crystal structure PDB4cy8 and related ligands described in Jensen, C. N. et al. “Structuresof the Apo and Fad-Bound Forms of 2-Hydroxybiphenyl 3-Monooxygenase(Hbpa) Locate Activity Hotspots Identified by Using Directed Evolution”,Chembiochem 16: 968 (2015); the crystal structure PDB 2hz0 and relatedligands described in Cowan-Jacob, S. W. et al. “Structural biologycontributions to the discovery of drugs to treat chronic myelogenousleukaemia”, Acta Crystallogr D Biol Crystallogr. 63(Pt 1):80-93 (2007);the crystal structure PDB 3pyy and related ligands described in Yang, J.et al. “Discovery and Characterization of a Cell-Permeable,Small-Molecule c-Abl Kinase Activator that Binds to the MyristoylBinding Site”, Chem. Biol. 18: 177-186 (2011); and, the crystalstructure PDB 5k5v and related ligands described in Kim, M. K., et al.“Structural basis for dual specificity of yeast N-terminal amidase inthe N-end rule pathway”, Proc. Natl. Acad Sci. U.S.A. 113: 12438-12443(2016).

FIG. 8JJJ presents examples of ABL2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 2xyn and related ligandsdescribed in Salah, E. et al. “Crystal Structures of Abl-Related Gene(Abl2) in Complex with Imatinib, Tozasertib (Vx-680), and a Type IInhibitor of the Triazole Carbothioamide Class”, J Med Chem. 54: 2359(2011); the crystal structure PDB 4xli and related ligands described inHa, B. H. et al. “Structure of the ABL2/ARG kinase in complex withdasatinib” Acta Crystallogr. Sect. F 71: 443-448 (2015); and the crystalstructure PDB 3gvu and related ligands described in Salah, E. et al.“The crystal structure of human ABL2 in complex with Gleevec”, to bepublished.

FIG. 8KKK-8MMM present examples of AKT1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Lippa, B. et al. “Synthesis and structure basedoptimization of novel Akt inhibitors Bioorg. Med Chem. Lett. 18:3359-3363 (2008); Freeman-Cook, K. D. et al. “Design of selective,ATP-competitive inhibitors of Akt”, J. Med Chem. 53: 4615-4622 (2010);Blake, J. F. et al “Discovery of pyrrolopyrimidine inhibitors of Akt”,Bioorg. Med Chem. Lett. 20: 5607-5612 (2010); Kallan, N.C. et al.“Discovery and SAR of spirochromane Akt inhibitors”, Bioorg. Med Chem.Lett. 21: 2410-2414 (2011); Lin, K “An ATP-Site On-Off Switch ThatRestricts Phosphatase Accessibility of Akt”, Sci. Signal. 5: ra37-ra37(2012); Addie, M. et al. “Discovery of4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide(AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases”, J.Med Chem. 56: 2059-2073 (2013); Wu, W. I., et al. “Crystal structure ofhuman AKT1 with an allosteric inhibitor reveals a new mode of kinaseinhibition. Plos One 5: 12913-12913 (2010); Ashwell, M. A. et al.“Discovery and optimization of a series of3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orallybioavailable, selective, and potent ATP-independent Akt inhibitors”, J.Med Chem. 55: 5291-5310 (2012); and, Lapierre, J. M. et al. “Discoveryof3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine(ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKTInhibitor”, J. Med Chem. 59: 6455-6469 (2016).

FIG. 8NNN-8OOO present examples of AKT2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structured PDB 2jdo and 2jdr andrelated ligands described in Davies, T. G. et al. “A StructuralComparison of Inhibitor Binding to Pkb, Pka and Pka-Pkb Chimera”, J Mol.Biol. 367: 882 (2007); the crystal structure PDB 2uw9 and relatedligands described in Saxty, G. et al “Identification of Inhibitors ofProtein Kinase B Using Fragment-Based Lead Discovery”, J. Med. Chem. 50:2293-2296 (2007); the crystal structure PDB 2×39 and 2xh5 and relatedligands described in Mchardy, T. et al. “Discovery of4-Amino-1-(7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl)Piperidine-4-Carboxamides asSelective, Orally Active Inhibitors of Protein Kinase B (Akt)”, J. Med.Chem. 53: 2239d (2010); the crystal structure PDB 3d03 and relatedligands described in Hadler, K. S. et al. “Substrate-promoted formationof a catalytically competent binuclear center and regulation ofreactivity in a glycerophosphodiesterase from Enterobacter aerogenes’,J. Am. Chem. Soc. 130: 14129-14138 (2008); and, the crystal structuresPDB 3e87, 3e8d and 3e88 and related ligands described in Rouse, M. B. etal. “Aminofurazans as potent inhibitors of AKT kinase” Bioorg. Med.Chem. Lett. 19: 1508-1511 (2009).

FIG. 8PPP presents examples of BMX Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 3sxr and 3sxr andrelated ligands described in Muckelbauer, J. et al. “X-ray crystalstructure of bone marrow kinase in the x chromosome: a Tec familykinase”, Chem. Biol. Drug Des. 78: 739-748 (2011).

FIG. 8QQQ-8SSS present examples of CSF1R Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 2i0v and 2ilm andrelated ligands described in Schubert, C. et al. “Crystal structure ofthe tyrosine kinase domain of colony-stimulating factor-1 receptor(cFMS) in complex with two inhibitors”, J. Biol. Chem. 282: 4094-4101(2007); the crystal structure PDB 3bea and related ligands described inHuang, H. et al. “Design and synthesis of a pyrido[2,3-d]pyrimidin-5-oneclass of anti-inflammatory FMS inhibitors”, Bioorg. Med. Chem. Lett. 18:2355-2361 (2008); the crystal structure PDB 3dpk and related ligandsdescribed in M. T., McKay, D. B. Overgaard, “Structure of the Elastaseof Pseudomonas aeruginosa Complexed with Phosphoramidon”, to bepublished; the crystal structures PDB 3krj and 3krl and related ligandsdescribed in Illig, C. R. et al. “Optimization of a Potent Class ofArylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading toAnti-inflammatory Clinical Candidate4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide(JNJ-28312141”, J. Med Chem. 54: 7860-7883 (2011); the crystal structurePDB 4r7h and related ligands described in Tap, W. D. et al.“Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-CellTumor: N Engl J Med 373: 428-437 (2015); the crystal structure PDB 31cdand 31coa and related ligands described in Meyers, M. J. et al.“Structure-based drug design enables conversion of a DFG-in bindingCSF-1R kinase inhibitor to a DFG-out binding mod”, Bioorg. Med Chem.Lett. 20: 1543-1547 (2010); the crystal structure PDB 4hw7 and relatedligands described in Zhang, C. et al. “Design and pharmacology of ahighly specific dual FMS and KIT kinase inhibitor”, Proc. Natl. AcadSci. USA 110: 5689-5694 (2013); and, the crystal structure PDB 4r7i andrelated ligands described in Tap, W. D. et al. “Structure-GuidedBlockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor”, N Engl J Med373: 428-437 (2015).

FIG. 8TTT presents examples of CSK Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Levinson, N. M. et al. “Structural basis for therecognition of c-Src by its inactivator Csk”, Cell 134: 124-134 (2008).

FIG. 8UUU-8YYY present examples of DDR1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 3zos and 4bkj andrelated ligands described in Canning, P. et al. “Structural MechanismsDetermining Inhibition of the Collagen Receptor Ddr1 by Selective andMulti-Targeted Type II Kinase Inhibitors”, J. Mol. Biol. 426: 2457(2014); the crystal structure PDB 4ckr and related ligands described inKim, H. et al. “Discovery of a Potent and Selective Ddr1 ReceptorTyrosine Kinase Inhibitor”, ACS Chem.Biol. 8: 2145 (2013); the crystalstructure PDB 5bvk, 5bvn and 5bvw and related ligands described inMurray, C. W et al. “Fragment-Based Discovery of Potent and SelectiveDDR1/2 Inhibitors”, ACS Med Chem. Lett. 6: 798-803 (2015); the crystalstructure PDB 5fdp and related ligands described in Wang, Z. et al.“Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides asSelective Discoidin Domain Receptor 1 (DDR1) Inhibitors”, J. Med Chem.59: 5911-5916 (2016); and, the crystal structure PDB 5fdx and relatedligands described in Bartual, S. G. et al. “Structure of DDR1 receptortyrosine kinase in complex with D2164 inhibitor at 2.65 Angstromsresolution”, to be published.

FIG. 8ZZZ-8CCCC present examples of EPHA2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 5i9x, 5i9y, 5ia0 and5ia1 and related ligands described in Heinzlmeir, S. et al. “ChemicalProteomics and Structural Biology Define EPHA2 Inhibition by ClinicalKinase Drug”, ACS Chem. Biol. 11: 3400-3411 (2016); the crystalstructure PDB 5i9z and related ligands described in Heinzlmeir, S. etal. “Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase withdanusertib (PHA739358)”, ACS Chem Biol 11 3400-3411 (2016); and, thecrystal structures PDB 5ia2, 5ia3, 5ia4, and 5ia5 and related ligandsdescribed in Heinzlmeir, S. et al. “Chemical Proteomics and StructuralBiology Define EPHA2 Inhibition by Clinical Kinase Drug”, ACS Chem.Biol. 11: 3400-3411 (2016).

FIG. 8DDDD-8FFFF present examples of EPHA3 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 4g2f and relatedligands described in Zhao, H. et al. “Discovery of a novel chemotype oftyrosine kinase inhibitors by fragment-based docking and moleculardynamics”, ACS Med Chem. Lett. 3: 834-838 (2012); the crystal structurePDB 4gk2 and 4gk3 and related ligands described in Lafleur, K. et al.“Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. CellularPotency Improvement and Binding Mode Validation by X-rayCrystallography”, J. Med Chem. 56: 84-96 (2013); the crystal structurePDB 4gk3 and related ligands described in Lafleur, K. et al.“Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. CellularPotency Improvement and Binding Mode Validation by X-rayCrystallography”, J. Med Chem. 56: 84-96 (2013); the crystal structurePDB 4p4c and 4p5q and related ligands described in Unzue, A. et al.“Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1/2 and II Eph TyrosineKinase Inhibitors: Structure-Based Design, Synthesis, and in VivoValidation”, J. Med Chem. 57: 6834-6844 (2014); the crystal structurePDB 4p5z and related ligands described in Unzue, A. et al.“Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1/2 and II Eph TyrosineKinase Inhibitors: Structure-Based Design, Synthesis, and in VivoValidation”, J. Med Chem. 57: 6834-6844 (2014); the crystal structurePDB 4twn and related ligands described in Dong, J. et al. “StructuralAnalysis of the Binding of Type I, I1/2, and II Inhibitors to EphTyrosine Kinases”, ACS Med. Chem. Lett. 6: 79-83 (2015); the crystalstructure PDB 3dzq and related ligands described in Walker, J. R.“Kinase Domain of Human Ephrin Type-A Receptor 3 (Epha3) in Complex withALW-II-38-3”, to be published.

FIG. 8GGGG presents examples of EPHA4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 2y60 and related ligandsdescribed in Clifton, I. J. et al. “The Crystal Structure ofIsopenicillin N Synthase withDelta((L)-Alpha-Aminoadipoyl)-(L)-Cysteinyl-(D)-Methionine RevealsThioether Coordination to Iron”, Arch. Biochem. Biophys. 516: 103 (2011)and the crystal structure PDB 2xyu and related ligands described in VanLinden, O. P et al. “Fragment Based Lead Discovery of Small MoleculeInhibitors for the Epha4 Receptor Tyrosine Kinase”, Eur. J. Med Chem.47: 493 (2012).

FIG. 8HHHH presents examples of EPHA7 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3dko and related ligandsdescribed in Walker, J. R. et al. “Kinase domain of human ephrin type-areceptor 7 (epha7) in complex with ALW-II-49-7”, to be published.

FIG. 8IIII-8LLLL presents examples of EPHB4 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 2vx1 and relatedligands described in Bardelle, C. et al. “Inhibitors of the TyrosineKinase Ephb4. Part 2: Structure-Based Discovery and Optimisation of3,5-Bis Substituted Anilinopyrimidines”, Bioorg. Med Chem. Lett. 18:5717(2008); the crystal structure PDB 2×9f and related ligands describedin Bardelle, C. et al. “Inhibitors of the Tyrosine Kinase Ephb4. Part 3:Identification of Non-Benzodioxole-Based Kinase Inhibitors”, Bioorg. MedChem. Lett. 20: 6242-6245 (2010); the crystal structure PDB 2xvd andrelated ligands described in Barlaam, B. et al. “Inhibitors of theTyrosine Kinase Ephb4. Part 4: Discovery and Optimization of a BenzylicAlcohol Series”, Bioorg. Med Chem. Lett. 21: 2207 (2011); the crystalstructure PDB 3zew and related ligands described in Overman, R. C. etal. “Completing the Structural Family Portrait of the Human EphbTyrosine Kinase Domains”, Protein Sci. 23: 627 (2014); the crystalstructure PDB 4aw5 and related ligands described in Kim, M. H. et al.“The Design, Synthesis, and Biological Evaluation of Potent ReceptorTyrosine Kinase Inhibitors”, Bioorg. Med Chem. Lett. 22: 4979 (2012);the crystal structure PDB 4bb4 and related ligands described inVasbinder, M. M. et al. “Discovery and Optimization of a Novel Series ofPotent Mutant B-Raf V600E Selective Kinase Inhibitors” J. Med Chem. 56:1996.”, (2013); the crystal structures PDB 2vwu, 2vwv and 2vww andrelated ligands described in Bardelle, C. et al “Inhibitors of theTyrosine Kinase Ephb4. Part 1: Structure-Based Design and Optimizationof a Series of 2,4-Bis-Anilinopyrimidines”, Bioorg. Med Chem. Lett. 18:2776-2780 (2008); the crystal structures PDB 2vwx, 2vwy, and 2vwz andrelated ligands described in Bardelle, C. et al. “Inhibitors of theTyrosine Kinase Ephb4. Part 2: Structure-Based Discovery andOptimisation of 3,5-Bis Substituted Anilinopyrimidines”, Bioorg. MedChem. Lett. 18: 5717 (2008); and, the crystal structure PDB 2vxo andrelated ligands described in Welin, M. et al. “Substrate Specificity andOligomerization of Human Gmp Synthetas”, J. Mol. Biol. 425: 4323 (2013).

FIG. 8MMMM presents examples of ERBB2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure and related ligandsdescribed in Aertgeerts, K. et al “Structural Analysis of the Mechanismof Inhibition and Allosteric Activation of the Kinase Domain of HER2Protein”, J. Biol. Chem. 286: 18756-18765 (2011) and the crystalstructure and related ligands described in Ishikawa, T. et al. “Designand Synthesis of Novel Human Epidermal Growth Factor Receptor 2(HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing aPyrrolo[3,2-d]pyrimidine Scaffold” J. Med. Chem. 54: 8030-8050 (2011).

FIG. 8NNNN presents examples of ERBB3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Littlefield, P. et al. “An ATP-CompetitiveInhibitor Modulates the Allosteric Function of the HER3 Pseudokinase”,Chem. Biol. 21: 453-458 (2014).

FIG. 8OOOO presents examples ERBB4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Qiu, C. et al. “Mechanism of Activation andInhibition of the HER4/ErbB4 Kinase”, Structure 16: 460-467 (2008) andWood, E. R. et al. “6-Ethynylthieno[3,2-d]- and6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiersof ErbB kinases”, Proc. Natl. Acad. Sci. Usa 105: 2773-2778 (2008).

FIG. 8PPPP-8QQQQ present examples of FES Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Filippakopoulos, P. et al “Structural Coupling ofSH2-Kinase Domains Links Fes and Abl Substrate Recognition and KinaseActivation.” Cell 134: 793-803 (2008) and Hellwig, S. et al.“Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase”, Chem.Biol. 19: 529-540 (2012).

FIG. 8RRRR presents examples of FYN Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Kinoshita, T. et. al. “Structure of human Fynkinase domain complexed with staurosporine”, Biochem. Biophys. Res.Commun. 346: 840-844 (2006).

FIG. 8SSSS-8VVVV present examples of GSG2 (Haspin) Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structures PDB 3e7v, PDB3f2n, 3fmd and related ligands described in Filippakopoulos, P. et al.“Crystal Structure of Human Haspin with a pyrazolo-pyrimidine ligand”,to be published; the crystal structure PDB 3iq7 and related ligandsdescribed in Eswaran, J. et al. “Structure and functionalcharacterization of the atypical human kinase haspin”, Proc. Natl. AcadSci. USA 106: 20198-20203 (2009); and, the crystal structure PDB 4qtcand related ligands described in Chaikuad, A. et al. “A unique inhibitorbinding site in ERK1/2 is associated with slow binding kinetics”, Nat.Chem. Biol. 10: 853-860 (2014).

FIG. 8WWWW-8AAAAA present examples of HCK Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 1qcf and related ligandsdescribed in Schindler, T. et al. “Crystal structure of Hck in complexwith a Src family-selective tyrosine kinase inhibitor”, Mol. Cell 3:639-648 (1999); the crystal structure PDB 2c0i and 2c0t and relatedligands described in Burchat, A. et al. “Discovery of A-770041, aSrc-Family Selective Orally Active Lck Inhibitor that Prevents OrganAllograft Rejection”, Bioorg. Med Chem. Lett. 16: 118 (2006); thecrystal structure PDB 2hk5 and related ligands described in Sabat, M. etal. “The development of 2-benzimidazole substituted pyrimidine basedinhibitors of lymphocyte specific kinase (Lck)”, Bioorg. Med Chem. Lett.16: 5973-5977 (2006); the crystal structures PDB 3vry, 3vs3, 3vs6, and3vs7 and related ligands described in Saito, Y. et al. “APyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells inVivo”, Sci Transl Med 5: 181ra52-181ra52 (2013); and, the crystalstructure PDB 4lud and related ligands described in Parker, L. J. et al“Kinase crystal identification and ATP-competitive inhibitor screeningusing the fluorescent ligand SKF86002”, Acta Crystallogr., Sect. D 70:392-404 (2014).

FIG. 8BBBBB-8FFFFF present examples of IGFIR Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 2oj9 and relatedligands described in Velaparthi, U. et al. “Discovery and initial SAR of3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-ones as inhibitors ofinsulin-like growth factor 1-receptor (IGF-1R)”, Bioorg. Med Chem. Lett.17: 2317-2321 (2007); the crystal structure PDB 3i81 and related ligandsdescribed in Wittman, M. D. et al. “Discovery of a 2,4-disubstitutedpyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-likegrowth factor receptor (IGF-1R) kinase in clinical development.”, J. MedChem. 52: 7360-7363 (2009); the crystal structure PDB 3nw5 and relatedligands described in Sampognaro, A. J. et al. “Proline isosteres in aseries of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors ofIGF-1R kinase and IR kinase”, Bioorg. Med Chem. Lett. 20: 5027-5030(2010); the crystal structure PDB 3qqu and related ligands described inBuchanan, J. L. et al. “Discovery of 2,4-bis-arylamino-1,3-pyrimidinesas insulin-like growth factor-1 receptor (IGF-1R) inhibitors”, Bioorg.Med Chem. Lett. 21: 2394-2399 (2011); the crystal structure PDB 4d2r andrelated ligands described in Kettle, J. G. et al. “Discovery andOptimization of a Novel Series of DyrklB Kinase Inhibitors to Explore aMek Resistance Hypothesis”. J. Med Chem. 58: 2834 (2015); the crystalstructure PDB 3fxq and related ligands described in Monferrer, D. et al.“Structural studies on the full-length LysR-type regulator TsaR fromComamonas testosteroni T-2 reveal a novel open conformation of thetetrameric LTTR fold”, Mol. Microbiol. 75: 1199-1214 (2010); the crystalstructure PDB 5fxs and related ligands described in Degorce, S. et al.“Discovery of Azd9362, a Potent Selective Orally Bioavailable andEfficacious Novel Inhibitor of Igf-R1”, to be published; the crystalstructure PDB 2zm3 and related ligands described in Mayer, S. C. et al.“Lead identification to generate isoquinolinedione inhibitors ofinsulin-like growth factor receptor (IGF-1R) for potential use in cancertreatment”, Bioorg. Med Chem. Lett. 18: 3641-3645 (2008); the crystalstructure PDB 3f5p and related ligands described in “Lead identificationto generate 3-cyanoquinoline inhibitors of insulin-like growth factorreceptor (IGF-1R) for potential use in cancer treatment” Bioorg. MedChem. Lett. 19: 62-66 (2009); the crystal structure PDB 31vp and relatedligands described in Nemecek, C. et al. “Design of Potent IGF1-RInhibitors Related to Bis-azaindoles” Chem. Biol. Drug Des. 76: 100-106(2010); the crystal structure PDB 3o23 and related ligands described inLesuisse, D. et al. “Discovery of the first non-ATP competitive IGF-1Rkinase inhibitors: Advantages in comparison with competitiveinhibitors”, Bioorg. Med Chem. Lett. 21: 2224-2228 (2011); the crystalstructure PDB 3d94 and related ligands described in Wu, J. et al.“Small-molecule inhibition and activation-loop trans-phosphorylation ofthe IGF1 receptor”, Embo J. 27: 1985-1994 (2008); and, the crystalstructure PDB 5hzn and related ligands described in Stauffer, F. et al.“Identification of a5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidineseries of IGF-1R inhibitors”, Bioorg. Med Chem. Lett. 26: 2065-2067(2016).

FIG. 8GGGGG-8JJJJJ present examples of INSR Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 2z8c and relatedligands described in Katayama, N. et al. “Identification of a keyelement for hydrogen-bonding patterns between protein kinases and theirinhibitors”, Proteins 73: 795-801 (2008); the crystal structure PDB 3ekkand related ligands described in Chamberlain, S. D. et al. “Discovery of4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: Potent inhibitors of theIGF-1R receptor tyrosine kinase”, (2009) Bioorg. Med Chem. Lett. 19:469-473; the crystal structure PDB 3ekn and related ligands described inChamberlain, S. D. et al. “Optimization of4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinaseinhibitors towards JNK selectivity”, Bioorg. Med Chem. Lett. 19: 360-364(2009); the crystal structure PDB 5els and related ligands described inSanderson, M. P. et al. “BI 885578, a Novel IGF1R/INSR Tyrosine KinaseInhibitor with Pharmacokinetic Properties That Dissociate AntitumorEfficacy and Perturbation of Glucose Homeostasis” Mol. Cancer Ther. 14:2762-2772”, (2015); the crystal structure PDB 3eta and related ligandsdescribed in Patnaik, S. et al. “Discovery of3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines as potent inhibitors of theinsulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase”, Bioorg.Med Chem. Lett. 19: 3136-3140 (2009); the crystal structure PDB 5hhw andrelated ligands described in Stauffer, F. et al. “Identification of a5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidineseries of IGF-1R inhibitors”, Bioorg. Med Chem. Lett. 26: 2065-2067(2016); and, the crystal structure PDB 4ibm and related ligandsdescribed in Anastassiadis, T. et al. “A highly selective dual insulinreceptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitorderived from an extracellular signal-regulated kinase (ERK) inhibitor”,J. Biol. Chem. 288: 28068-28077 (2013).

FIG. 8KKKKK-8PPPPP present examples of HBV Targeting Ligands wherein Ris the point at which the Linker is attached, Y is methyl or isopropyl,and X is N or C. For additional examples and related ligands, see,Weber, O.; et al. “Inhibition of human hepatitis B virus (HBV) by anovel non-nucleosidic compound in a transgenic mouse model.” AntiviralRes.54, 69-78 (2002); Deres, K.; et al. “Inhibition of hepatitis B virusreplication by drug-induced depletion of nucleocapsids.” Science, 299,893-896 (2003); Stray, S. J.; Zlotnick, A. “BAY 41-4109 has multipleeffects on Hepatitis B virus capsid assembly.” J. Mol. Recognit. 19,542-548 (2006); Stray, S. J.; et al. “heteroaryldihydropyrimidineactivates and can misdirect hepatitis B virus capsid assembly.” Proc.Natl. Acad. Sci. U.S.A, 102, 8138-8143 (2005); Guan, H.; et al. “Thenovel compound Z060228 inhibits assembly of the HBV capsid.” Life Sci.133, 1-7 (2015); Wang, X. Y.; et al. “In vitro inhibition of HBVreplication by a novel compound, GLS4, and its efficacy againstadefovir-dipivoxil-resistant HBV mutations.” Antiviral Ther. 17, 793-803(2012); Klumpp, K.; et al. “High-resolution crystal structure of ahepatitis B virus replication inhibitor bound to the viral coreprotein.” 112, 15196-15201 (2015); Qiu, Z.; et al. “Design and synthesisof orally bioavailable 4-methyl heteroaryldihydropyrimidine basedhepatitis B virus (HBV) capsid inhibitors.” J. Med. Chem. 59, 7651-7666(2016); Zhu, X.; et al.“2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives asanti-HBV agents targeting at capsid assembly.” Bioorg. Med. Chem. Lett.20, 299-301 (2010); Campagna, M. R.; et al. “Sulfamoylbenzamidederivatives inhibit the assembly of hepatitis B virus nucleocapsids.” J.Virol. 87, 6931-6942 (2013); Campagna, M. R.; et al. “Sulfamoylbenzamidederivatives inhibit the assembly of hepatitis B virus nucleocapsids.” J.Virol. 87, 6931-6942 (2013); WO 2013096744 A1 titled “Hepatitis Bantivial agents”; WO 2015138895 titled “Hepatitis B core proteinallosteric modulators”; Wang, Y. J.; et al. “A novel pyridazinonederivative inhibits hepatitis B virus replication by inducinggenome-free capsid formation.” Antimicrob. Agents Chemother. 59,7061-7072 (2015); WO 2014033167 titled “Fused bicyclic sulfamoylderivatives for the treatment of hepatitis”; U.S. 20150132258 titled“Azepane derivatives and methods of treating hepatitis B infections”;and, WO 2015057945 “Hepatitis B viral assembly effector”.

FIG. 9 is a dendrogram of the human bromodomain family of proteinsorganized into eight subfamilies, which are involved in epigeneticsignaling and chromatin biology. Any of the proteins of the bromodomainfamily in FIG. 9 can be selected as a Target Protein according to thepresent invention.

DETAILED DESCRIPTION I. Definitions

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein may be in the formof a racemate, enantiomer, mixture of enantiomers, diastereomer, mixtureof diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if eachis specifically described unless specifically excluded by context.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed.

The present invention includes compounds of Formula I, Formula II,Formula III, and Formula IV with at least one desired isotopicsubstitution of an atom, at an amount above the natural abundance of theisotope, i.e., enriched. Isotopes are atoms having the same atomicnumber but different mass numbers, i.e., the same number of protons buta different number of neutrons. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine andiodine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P ³⁵S, ³⁶Cl, and¹²⁵I respectively. In one non-limiting embodiment, isotopically labelledcompounds can be used in metabolic studies (with, for example ¹⁴C),reaction kinetic studies (with, for example ²H or ³H), detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the schemes or in the examplesand preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one non-limiting embodiment, deuterium is 90, 95 or 99%enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom fora deuterium atom can be provided in any compound of Formula I, FormulaII, Formula III, Formula IV, Formula V or Formula VI. In onenon-limiting embodiment, the substitution of a hydrogen atom for adeuterium atom occurs within one or more groups selected from any of thevariables described herein, Linker, and Targeting Ligand. For example,when any of the groups are, or contain for example through substitution,methyl, ethyl, or methoxy, the alkyl residue may be deuterated (innon-limiting embodiments, CDH₂, CD₂H, CD₃, CH₂CD₃, CD₂CD₃, CHDCH₂D,CH₂CD₃, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃ etc.). In certain otherembodiments, when two substituents are combined to form a cycle theunsubstituted carbons may be deuterated.

The compound of the present invention may form a solvate with a solvent(including water). Therefore, in one non-limiting embodiment, theinvention includes a solvated form of the compound. The term “solvate”refers to a molecular complex of a compound of the present invention(including a salt thereof) with one or more solvent molecules.Non-limiting examples of solvents are water, ethanol, isopropanol,dimethyl sulfoxide, acetone and other common organic solvents. The term“hydrate” refers to a molecular complex comprising a compound of theinvention and water. Pharmaceutically acceptable solvates in accordancewith the invention include those wherein the solvent may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO. A solvate can be in a liquidor solid form.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the carbonyl (C═O) group.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbongroup. In one non-limiting embodiment, the alkyl group contains from 1to about 12 carbon atoms, more generally from 1 to about 6 carbon atomsor from 1 to about 4 carbon atoms. In one non-limiting embodiment, thealkyl contains from 1 to about 8 carbon atoms. In certain embodiments,the alkyl is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, or C₁-C₆. The specified rangesas used herein indicate an alkyl group having each member of the rangedescribed as an independent species. For example, the term C₁-C₆ alkylas used herein indicates a straight or branched alkyl group having from1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each ofthese is described as an independent species and therefore each subsetis considered separately disclosed. For example, the term C₁-C₄ alkyl asused herein indicates a straight or branched alkyl group having from 1,2, 3, or 4 carbon atoms and is intended to mean that each of these isdescribed as an independent species. Examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl,n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and2,3-dimethylbutane. In an alternative embodiment, the alkyl group isoptionally substituted. The term “alkyl” also encompasses cycloalkyl orcarbocyclic groups. For example, when a term is used that includes “alk”then “cycloalkyl” or “carbocyclic” can be considered part of thedefinition, unless unambiguously excluded by the context. For exampleand without limitation, the terms alkyl, alkoxy, haloalkyl, etc. can allbe considered to include the cyclic forms of alkyl, unless unambiguouslyexcluded by context.

“Alkenyl” is a linear or branched aliphatic hydrocarbon groups havingone or more carbon-carbon double bonds that may occur at a stable pointalong the chain. The specified ranges as used herein indicate an alkenylgroup having each member of the range described as an independentspecies, as described above for the alkyl moiety. Examples of alkenylradicals include, but are not limited to ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies“cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z”alkenyl geometry. In an alternative embodiment, the alkenyl group isoptionally substituted. The term “Alkenyl” also encompasses cycloalkylor carbocyclic groups possessing at least one point of unsaturation.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain. The specified ranges as used hereinindicate an alkynyl group having each member of the range described asan independent species, as described above for the alkyl moiety.Examples of alkynyl include, but are not limited to, ethynyl, propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. Inan alternative embodiment, the alkynyl group is optionally substituted.The term “Alkynyl” also encompasses cycloalkyl or carbocyclic groupspossessing at least one triple bond.

“Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example,can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety,or an indicated number of carbon atoms, for example C₁-C₂alkylene,C₁-C₃alkylene, C₁-C₄alkylene, C₁-C₅alkylene, or C₁-C₆alkylene.“Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbondouble bond.

Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbonmoiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkenylene. “Alkynylene” is a bivalent hydrocarbon having at leastone carbon-carbon triple bond.

Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbonmoiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkynylene.

“Halo” and “Halogen” refers to fluorine, chlorine, bromine or iodine.

“Haloalkyl” is a branched or straight-chain alkyl groups substitutedwith 1 or more halo atoms described above, up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl groups include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perhaloalkyl” means an alkyl group having all hydrogen atoms replacedwith halogen atoms. Examples include but are not limited to,trifluoromethyl and pentafluoroethyl.

“Chain” indicates a linear chain to which all other chains, long orshort or both, may be regarded as being pendant. Where two or morechains could equally be considered to be the main chain, “chain” refersto the one which leads to the simplest representation of the molecule.

“Haloalkoxy” indicates a haloalkyl group as defined herein attachedthrough an oxygen bridge (oxygen of an alcohol radical).

“Heterocycloalkyl” is an alkyl group as defined herein substituted witha heterocyclo group as defined herein.

“Arylalkyl” is an alkyl group as defined herein substituted with an arylgroup as defined herein.

“Heteroarylalkyl” is an alkyl group as defined herein substituted with aheteroaryl group as defined herein.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 7L electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. The one or more fused carbocyclyl or heterocyclyl groups can be4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclylor heterocyclyl groups that optionally contain 1, 2, or 3 heteroatomsindependently selected from nitrogen, oxygen, phosphorus, sulfur,silicon and boron, to form, for example, a 3,4-methylenedioxyphenylgroup. In one non-limiting embodiment, aryl groups are pendant. Anexample of a pendant ring is a phenyl group substituted with a phenylgroup. In an alternative embodiment, the aryl group is optionallysubstituted as described above. In certain embodiments, the aryl groupis an unsubstituted C₆₋₁₄ aryl. In certain embodiments, the aryl groupis a substituted C₆₋₁₄ aryl. An aryl group may be optionally substitutedwith one or more functional groups that include but are not limited to,halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, andheterocyclo.

The term “heterocyclyl” (or “heterocyclo”) includes saturated, andpartially saturated heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen.Heterocyclic rings comprise monocyclic 3-8 membered rings, as well as5-16 membered bicyclic ring systems (which can include bridged fused andspiro-fused bicyclic ring systems). It does not include rings containing—O—O—.—O—S— or —S—S— portions. Said “heterocyclyl” group may beoptionally substituted, for example, with 1, 2, 3, 4 or moresubstituents that include but are not limited to, hydroxyl, Boc, halo,haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. Examples ofsaturated heterocyclo groups include saturated 3- to 6-memberedheteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g.pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl];saturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partiallysaturated heterocyclyl radicals include but are not limited to,dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.Examples of partially saturated and saturated heterocyclo groups includebut are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl.

Heterocyclo groups also include radicals where heterocyclic radicals arefused/condensed with aryl or heteroaryl radicals: such as unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indoline, isoindoline, unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.

The term “heteroaryl” denotes aryl ring systems that contain one or moreheteroatoms selected from O, N and S, wherein the ring nitrogen andsulfur atom(s) are optionally oxidized, and nitrogen atom(s) areoptionally quarternized. Examples include but are not limited to,unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, IH-1,2,3-triazolyl, 2H-1,2,3-triazolyl];unsaturated 5- to 6-membered heteromonocyclic groups containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5to 6-membered heteromonocyclic groups containing a sulfur atom, forexample, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “optionally substituted” denotes the substitution of a groupherein by a moiety including, but not limited to, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ cycloalkenyl, C₁-C₁₂heterocycloalkyl, C₃-C₁₂ heterocycloalkenyl, C₁-C₁₀ alkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, arylamino, diarylamino, C₁-C₁₀ alkylsulfonamino,arylsulfonamino, C₁-C₁₀ alkylimino, arylimino, C₁-C₁₀ alkylsulfonimino,arylsulfonimino, hydroxyl, halo, thio, C₁-C₁₀ alkylthio, arylthio,C₁-C₁₀ alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl,amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl,acyloxy, carboxyl, and carboxylic ester.

In one alternative embodiment any suitable group may be present on a“substituted” or “optionally substituted” position if indicated thatforms a stable molecule and meets the desired purpose of the inventionand includes, but is not limited to, e.g., halogen (which canindependently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido;alkanoyl (such as a C₂-C₆ alkanoyl group); carboxamide; alkyl,cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkylincluding those having one or more thioether linkages; alkylsulfinyl;alkylsulfonyl groups including those having one or more sulfonyllinkages; aminoalkyl groups including groups having more than one Natoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ringeither substituted or unsubstituted); arylalkyl having for example, 1 to3 separate or fused rings and from 6 to about 14 or 18 ring carbonatoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, forexample, having 1 to 3 separate or fused rings with benzyloxy being anexemplary arylalkoxy group; or a saturated or partially unsaturatedheterocycle having 1 to 3 separate or fused rings with one or more N, Oor S atoms, or a heteroaryl having 1 to 3 separate or fused rings withone or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl,quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl,thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl,indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, andpyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy,alkyl, alkoxy, halogen and amino. In certain embodiments “optionallysubstituted” includes one or more substituents independently selectedfrom halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH₂, alkylincluding C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkynyl includingC₂-C₆alkynyl, —C₁-C₆alkoxy, alkanoyl including C₂-C₆alkanoyl,C₁-C₆alkylester, (mono-and di-C₁-C₆alkylamino)C₀-C₂alkyl, haloalkylincluding C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl, ester, carbamate, urea,sulfonamide,—C₁-C₆alkyl(heterocyclo), C₁-C₆alkyl(heteroaryl),—C₁-C₆alkyl(C₃-C₇cycloalkyl), O—C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂,phosphate, phosphonate and haloalkoxy including C₁-C₆haloalkoxy.

“Aliphatic” refers to a saturated or unsaturated, straight, branched, orcyclic hydrocarbon. “Aliphatic” is intended herein to include, but isnot limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties, and thus incorporates each of these definitions.In one embodiment, “aliphatic” is used to indicate those aliphaticgroups having 1-20 carbon atoms. The aliphatic chain can be, forexample, mono-unsaturated, di-unsaturated, tri-unsaturated, orpolyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in acis or trans configuration. In one embodiment, the aliphatic groupcontains from 1 to about 12 carbon atoms, more generally from 1 to about6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, thealiphatic group contains from 1 to about 8 carbon atoms. In certainembodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅ or C₁-C₆.The specified ranges as used herein indicate an aliphatic group havingeach member of the range described as an independent species. Forexample, the term C₁-C₆ aliphatic as used herein indicates a straight orbranched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or6 carbon atoms and is intended to mean that each of these is describedas an independent species. For example, the term C₁-C₄ aliphatic as usedherein indicates a straight or branched alkyl, alkenyl, or alkynyl grouphaving from 1, 2, 3, or 4 carbon atoms and is intended to mean that eachof these is described as an independent species. In one embodiment, thealiphatic group is substituted with one or more functional groups thatresults in the formation of a stable moiety.

The term “heteroaliphatic” refers to an aliphatic moiety that containsat least one heteroatom in the chain, for example, an amine, carbonyl,carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus,silicon, or boron atoms in place of a carbon atom. In one embodiment,the only heteroatom is nitrogen. In one embodiment, the only heteroatomis oxygen. In one embodiment, the only heteroatom is sulfur.“Heteroaliphatic” is intended herein to include, but is not limited to,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment,“heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. In one embodiment, the heteroaliphatic group is optionallysubstituted in a manner that results in the formation of a stablemoiety. Nonlimiting examples of heteroaliphatic moieties arepolyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide,polyglycolide, thioether, ether, alkyl-heterocycle-alkyl,—O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like. A “dosage form” canalso include an implant, for example an optical implant.

An “effective amount” as used herein, means an amount which provides atherapeutic or prophylactic benefit.

As used herein “endogenous” refers to any material from or producedinside an organism, cell, tissue or system.

As used herein, the term “exogenous” refers to any material introducedfrom or produced outside an organism, cell, tissue or system.

By the term “modulating,” as used herein, is meant mediating adetectable increase or decrease in the level of a response in a subjectcompared with the level of a response in the subject in the absence of atreatment or compound, and/or compared with the level of a response inan otherwise identical but untreated subject. The term encompassesperturbing and/or affecting a native signal or response therebymediating a beneficial therapeutic response in a subject, preferably, ahuman.

“Parenteral” administration of an immunogenic composition includes,e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), orintrasternal injection, or infusion techniques.

As used herein, the terms “peptide,” “polypeptide,” and “protein” areused interchangeably, and refer to a compound comprised of amino acidresidues covalently linked by peptide bonds. A protein or peptide mustcontain at least two amino acids, and no limitation is placed on themaximum number of amino acids that can comprise a protein's or peptide'ssequence. Polypeptides include any peptide or protein comprising two ormore amino acids joined to each other by peptide bonds. As used herein,the term refers to both short chains, which also commonly are referredto in the art as peptides, oligopeptides and oligomers, for example, andto longer chains, which generally are referred to in the art asproteins, of which there are many types. “Polypeptides” include, forexample, biologically active fragments, substantially homologouspolypeptides, oligopeptides, homodimers, heterodimers, variants ofpolypeptides, modified polypeptides, derivatives, analogs, fusionproteins, among others. The polypeptides include natural peptides,recombinant peptides, synthetic peptides, or a combination thereof.

To “treat” a disease as the term is used herein, means to reduce thefrequency or severity of at least one sign or symptom of a disease ordisorder experienced by a subject.

Ranges: throughout this disclosure, various aspects of the invention canbe presented in a range format. It should be understood that thedescription in range format is merely for convenience and should not beconstrued as a limitation on the scope of the invention. The descriptionof a range should be considered to have specifically disclosed all thepossible subranges as well as individual numerical values within thatrange. For example, description of a range such as from 1 to 6 should beconsidered to have specifically disclosed subranges such as from 1 to 3,from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., aswell as individual numbers within that range, for example, 1, 2, 2.7, 3,4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

As used herein, “pharmaceutical compositions” are compositionscomprising at least one active agent, and at least one other substance,such as a carrier. “Pharmaceutical combinations” are combinations of atleast two active agents which may be combined in a single dosage form orprovided together in separate dosage forms with instructions that theactive agents are to be used together to treat any disorder describedherein.

As used herein, “pharmaceutically acceptable salt” is a derivative ofthe disclosed compound in which the parent compound is modified bymaking inorganic and organic, non-toxic, acid or base addition saltsthereof. The salts of the present compounds can be synthesized from aparent compound that contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting freeacid forms of these compounds with a stoichiometric amount of theappropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate, or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, non-aqueous media like ether,ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, wherepracticable. Salts of the present compounds further include solvates ofthe compounds and of the compound salts.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like, or using a differentacid that produces the same counterion. Lists of additional suitablesalts may be found, e.g., in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term “carrier” applied to pharmaceutical compositions/combinationsof the invention refers to a diluent, excipient, or vehicle with whichan active compound is provided.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, non-toxic and neither biologically nor otherwiseinappropriate for administration to a host, typically a human. In oneembodiment, an excipient is used that is acceptable for veterinary use.

A “patient” or “host” or “subject” is a human or non-human animal inneed of treatment or prevention of any of the disorders as specificallydescribed herein, for example that is modulated by a natural (wild-type)or modified (non-wild type) protein that can be degraded according tothe present invention, resulting in a therapeutic effect. Typically, thehost is a human. A “host” may alternatively refer to for example, amammal, primate (e.g., human), cow, sheep, goat, horse, dog, cat,rabbit, rat, mice, fish, bird and the like.

A “therapeutically effective amount” of a pharmaceuticalcomposition/combination of this invention means an amount effective,when administered to a host, to provide a therapeutic benefit such as anamelioration of symptoms or reduction or diminution of the diseaseitself.

II. Compounds

In one aspect of the present invention a compound of Formula I orFormula II is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative,prodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition;wherein:

the variables are as defined above, wherein in certain embodiments thecompound has at least one of a, b, c, d, e, f, g, h, i, j, k, l, or m:

-   -   a. n is 1 or 2;    -   b. at least one of R¹, R², R³, or R⁴ is alkyl;    -   c. R¹ and R² form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   d. R³ and R⁴ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   e. R⁶ and R⁷ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   f. R⁸ and R⁹ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   g. R¹ and R³ form a 1 or 2 carbon bridged ring;    -   h. R¹ and R¹³ form a 3, 4, 5, or 6 carbon fused ring;    -   i. R⁴ and R¹³ form a 1 or 2 carbon bridged ring;    -   j. A is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂;    -   k. A′ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂    -   l. A″ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂; or    -   m. X is O, or S.

Non-limiting examples of compounds of Formula I include:

Additional non-limiting examples of compounds of Formula I include:

In one embodiment of the present invention

is selected from:

In an additional embodiment the Degronimer of Formula I is selectedfrom:

In an additional embodiment the Degronimer of Formula I is selectedfrom:

In an additional embodiment the Degronimer of Formula I is selectedfrom:

Non limiting examples of compounds of Formula II include:

In another aspect of the present invention a compound of Formula III isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative,prodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof; wherein the variablesare as defined herein.

Non limiting examples of compounds of Formula III include:

Additional non limiting examples of compounds of Formula III include:

In another aspect of the present invention a compound of Formula IV orFormula V is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative,prodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition;wherein:

the variables are as defined above and wherein in certain embodiments,a, b, c, d, e, f, g, h, i, or j is required:

-   -   a. R¹ and R² form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   b. R³ and R⁴ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   c. R⁶ and R⁷ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   d. R⁸ and R⁹ form a 4, 5, or 6 membered spiroheterocycle or 3,        4, 5, or 6 membered spirocarbocycle;    -   e. R¹ and R³ form a 1 or 2 carbon bridged ring;    -   f. R¹ and R¹³ form a 3, 4, 5, or 6 membered fused ring;    -   g. R⁴ and R¹³ form a 1 or 2 carbon bridged ring;    -   h. A is P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl,        P(O)OH, or P(O)NH₂;    -   i. A′ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂; or    -   j. A″ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂.

Non limiting examples of compounds of Formula IV include:

Additional non-limiting examples of compounds of Formula IV include:

In an additional embodiment the Degronimer of Formula IV is selectedfrom:

In an additional embodiment the Degronimer of Formula IV is selectedfrom:

In an additional embodiment the Degronimer of Formula IV is selectedfrom:

Non-limiting examples of compounds of Formula V include:

In another aspect of the present invention a compound of Formula VI isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative,prodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition; wherein:

A is CR⁸R⁹, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

A′ is CR¹R², C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

A″ is CR³R⁴, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

X is independently NH, NR¹¹, CH₂, CHR¹², C(R¹²)₂, O, or S;

n is 0, 1, 2, 3, 4, or 5;

m is 1 or 3;

is a single or double bond;

R¹, R², R³, R⁴, R⁶, R¹, R⁸, R⁹, and R¹³ are independently selected fromhydrogen, alkyl, hydroxyl, alkoxy, amine, —NHalkyl, —Nalkyl₂

or R¹ and R² form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-,5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O;

or R³ and R⁴ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-,5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O;

or R⁶ and R⁷ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-,5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O;

or R⁸ and R⁹ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-,5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O;

or R¹ and R³ form a 1 or 2 carbon bridged ring;

or R¹ and R⁷ form a 1 or 2 carbon bridged ring;

or R³ and R⁷ form a 1 or 2 carbon bridged ring;

or R¹³ and R¹ form a 3, 4, 5, or 6 carbon fused ring;

or R¹³ and R⁴ form a 1 or 2 carbon bridged ring;

or R¹³ and R⁵ form a 3, 4, 5, or 6 carbon fused ring wherein R⁵ is onthe carbon alpha to R¹³ or a 1, 2, 3, or 4 carbon bridged ring whereinR⁵ is not on the carbon alpha to R¹³;

in a typical embodiment W¹ is C═O;

in another typical embodiment W² is C═O;

in another typical embodiment both W¹ and W² are C═O and X is NH;

R⁵ is selected at each instance from: alkyl, alkene, alkyne, halogen,hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl)₂, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO2aryl, —NHSO₂alkenyl,—N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, and haloalkyl;

or two R⁵ substituents together with the carbon atom(s) to which theyare bound can form a 3, 4, 5 or 6 membered ring;

Q¹, Q², Q³, and Q⁴ are independently selected from CH, CR¹², and N;

no more than three of Q¹, Q², Q³, and Q⁴ are N;

R¹¹ is independently selected from alkyl, alkenyl, alkynyl, C(O)H,—C(O)OH, —C(O)alkyl, —C(O)Oalkyl;

R¹² is independently selected from alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)alkyl,—C(O)Oalkyl, —NHalkyl, —N(alkyl)₂, —NHSO₂alkyl, —N(alkyl)SO₂alkyl,—NHSO₂aryl, —N(alkyl)SO₂aryl, —NHSO₂alkenyl, —N(alkyl)SO₂alkenyl,—NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, cyano, nitro, nitroso, —SH, —Salkyl,and haloalkyl; wherein a, b, c, d, e, f, g, h, i, j, k, l, or m isrequired:

-   -   a. m is 3 and n is not 0;    -   b. R¹ and R² form a spirocycle;    -   c. R³ and R⁴ form a spirocycle;    -   d. R⁶ and R⁷ form a spirocycle;    -   e. R⁷ and R⁹ form a spirocycle;    -   f. R¹ and R³ form a 1 or 2 carbon bridged ring;    -   g. R¹ and R¹³ form a 3, 4, 5, or 6 carbon fused ring;    -   h. R⁴ and R¹³ form a 1 or 2 carbon bridged ring;    -   i. R¹³ and R⁵ form a 3, 4, 5, or 6 carbon fused ring;    -   j. R¹³ and R⁵ form a 1 or 2 carbon bridged ring;    -   k. A is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂;    -   l. A′ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂; or    -   m. A″ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,        P(O)alkyl, P(O)OH, or P(O)NH₂.

Non limiting examples of compounds of Formula VI include:

Additional non limiting examples of compounds of Formula VI include:

In one embodiment the

moiety of the Formulas above is selected from:

In one embodiment, a Linker is bonded to a heterocyclic Degron and aTargeting Ligand and the resulting molecule has a stable shelf life forat least 2 months, 3 months, 6 months or 1 year as part of apharmaceutically acceptable dosage form, and itself is pharmaceuticallyacceptable.

Linker

A Linker is included in the Degronimers of Formula I, II, and III.Linker is a bond or a chemically stable group that attaches a Degron toa Targeting Ligand.

Any of the Linkers described herein can be used in either direction,i.e., either the left end is linked to the Degron and the right end tothe Target Linker, or the left end is linked to the Target Linker andthe right end is linked to the Degron. According to the invention, anydesired linker can be used as long as the resulting compound has astable shelf life for at least 2 months, 3 months, 6 months or 1 year aspart of a pharmaceutically acceptable dosage form, and itself ispharmaceutically acceptable.

In a typical embodiment, the Linker has a chain of 2 to 14, 15, 16, 17,18 or 20 or more carbon atoms of which one or more carbons can bereplaced by a heteroatom such as O, N, S, or P. In certain embodimentsthe chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 or 20 contiguous atoms in the chain. For example, the chain mayinclude 1 or more ethylene glycol units that can be contiguous,partially contiguous or non-contiguous (for example, 2, 3, 4, 5, 6, 7,8, 9, 10, 11 or 12 ethylene glycol units). In certain embodiments thechain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains which canhave branches which can be independently alkyl, heteroalkyl, aryl,heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkylor heterocyclic substituents.

In other embodiments, the linker can include or be comprised of one ormore of ethylene glycol, propylene glycol, lactic acid and/or glycolicacid. In general, propylene glycol adds hydrophobicity, while propyleneglycol adds hydrophilicity. Lactic acid segments tend to have a longerhalf-life than glycolic acid segments. Block and random lacticacid-co-glycolic acid moieties, as well as ethylene glycol and propyleneglycol, are known in the art to be pharmaceutically acceptable and canbe modified or arranged to obtain the desired half-life andhydrophilicity. In certain aspects, these units can be flanked orinterspersed with other moieties, such as aliphatic, including alkyl,heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., asdesired to achieve the appropriate drug properties.

In one embodiment, the Linker is a moiety selected from Formula LI,Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, andFormula LVII:

wherein:

X¹ and X² are independently selected from bond, NH, NR²⁵, CH₂, CHR²⁵,C(R²⁵)₂, O, and S;

R²⁰, R²¹, R²², R²³, and R²⁴ are independently selected from bond, alkyl,—C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO₂—, —S(O)—,—C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—,—NH—, —N(alkyl)-, —CH(—O—R²⁶)—, —CH(—NHR²⁵)—, —CH(—NH₂)—, —CH(—NR²⁵ ₂)—,—C(—O—R²⁶)alkyl-, —C(—NHR²⁵)alkyl-, —C(—NH₂)alkyl-, —C(—NR²⁵ ₂)alkyl-,—C(R⁴R⁴)—, -alkyl(R²⁷)-alkyl(R²⁸)—, —C(R²⁷R²⁸)—, —P(O)(OR²⁶)O—,—P(O)(OR²⁶)—, —NHC(O)NH—, —N(R²⁵)C(O)N(R²⁵)—, —N(H)C(O)N(R²⁵)—,polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl,alkoxy, and alkyne;

or R²⁰, R²¹, R²², R²³, and R²⁴ can in addition to those above beindependently selected from heteroarylalkyl, aryl, arylalkyl,heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropyleneglycol, lactic acid, glycolic acid, carbocycle, or —O—(CH₂)₁₋₁₂—O—,—NH—(CH₂)₁₋₁₂—NH—, —NH—(CH₂)₁₋₁₂—O—, or —O—(CH₂)₁₋₁₂—NH—,—S—(CH₂)₁₋₁₂—O—, —O—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—NH—,—NH—(CH₂)₁₋₁₂—S—, (and wherein the 1-12 can be independently 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12, and wherein one or more of the CH₂ or NHcan be modified by substitution of a H for a methyl, ethyl, cyclopropyl,F (if on carbon), etc, as described herein), and optionally, aheteroatom, heteroalkyl, aryl, heteroaryl or cycloaliphatic group isinterspersed in the chain). Certain nonlimiting examples include—O—CH(CH₃)—CH(CH₃)CH—O—, —O—CH₂—CH(CH₃)CH—O—, —O—CH(CH₃)—CH₂CH—O—, etc.

each of which R²⁰, R²¹, R²², R²³, and R²⁴ is optionally substituted withone or more substituents selected from R¹⁰¹ or alternatively asdescribed in Section 1. Definitions;

R²⁵ is selected at each instance from: alkyl, —C(O)H, —C(O)OH,—C(O)alkyl, —C(O)Oalkyl, alkenyl, or alkynyl or alternatively can bealiphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic;

R²⁶ is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, andalkyne; or in addition to these can also be selected from aryl,heteroaryl, heterocyclic, aliphatic and heteroaliphatic;

R²⁷ and R²⁸ are independently selected from hydrogen, alkyl, amine, ortogether with the carbon atom to which they are attached, form C(O),C(S), C═CH₂, a C₃-C₆ spirocarbocycle, or a 4-, 5-, or 6-memberedspiroheterocycle comprising 1 or 2 heteroatoms selected from N and O, orform a 1 or 2 carbon bridged ring;

R⁴ is independently selected from hydrogen, alkyl, hydroxyl, alkoxy,amine, —NH(aliphatic, including alkyl), —Nalkyl₂;

R¹⁰¹ is independently selected at each occurrence from hydrogen, alkyl,alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl,heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy,heteroaryloxy, CN, —COOalkyl, COOH, NO₂, F, Cl, Br, I, CF₃, NH₂,NHalkyl, N(alkyl)₂, aliphatic, heteroaliphatic; and in addition to thesecan also be selected from aliphatic and heteroaliphatic.

In an additional embodiment, the Linker is a moiety selected fromFormula LVIII, LIX, and LX:

wherein each variable is as it is defined in Formula LI. In alternativeembodiments of LVIII, LIX and LX, a carbocyclic ring is used in place ofthe heterocycle.

The following are non-limiting examples of Linkers that can be used inthis invention. Based on this elaboration, those of skill in the artwill understand how to use the full breadth of Linkers that willaccomplish the goal of the invention.

As certain non-limiting examples, Formula LI, Formula LII, Formula LIII,Formula LIV, Formula LV, Formula LVI, or Formula LVII include:

In an additional embodiment Linker is selected from:

In an additional embodiment Linker is selected from:

In one embodiment X¹ is attached to the Targeting Ligand. In anotherembodiment X² is attached to the Targeting Ligand.

Non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

In additional embodiments, the Linker group is an optionally substituted(poly)ethylene glycol having at least 1, at least 2, at least 3, atleast 4, at least 5, at least 6, at least 7, at least 8, at least 9, atleast 10, ethylene glycol units, or optionally substituted alkyl groupsinterspersed with optionally substituted, O, N, S, P or Si atoms. Incertain embodiments, the Linker is flanked, substituted, or interspersedwith an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. Incertain embodiments, the Linker may be asymmetric or symmetrical. Insome embodiments, the Linker is a substituted or unsubstitutedpolyethylene glycol group ranging in size from about 1 to about 12ethylene glycol units, between 1 and about 10 ethylene glycol units,about 2 about 6 ethylene glycol units, between about 2 and 5 ethyleneglycol units, between about 2 and 4 ethylene glycol units. In any of theembodiments of the compounds described herein, the Linker group may beany suitable moiety as described herein.

In additional embodiments, the Linker is selected from:—NR⁶¹(CH₂)_(n1)-(lower alkyl)-, —NR⁶¹(CH₂)_(n1)-(lower alkoxyl)-,—NR⁶¹(CH₂)_(n1)-(lower alkoxyl)-OCH₂—, —NR⁶¹(CH₂)_(n1)-(loweralkoxyl)-(lower alkyl)-OCH₂—, —NR⁶¹(CH₂)_(n1)-(cycloalkyl)-(loweralkyl)-OCH₂—, —NR⁶¹(CH₂)_(n1)-(heterocycloalkyl)-,—NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-O—CH₂—,—NR⁶¹(CH₂CH₂O)_(n1)-(heterocycloalkyl)-O—CH₂—,—NR⁶¹(CH₂CH₂O)_(n1)-Aryl-O—CH₂—,—NR⁶¹(CH₂CH₂O)_(n1)-(heteroaryl)-O—CH₂—,—NR⁶¹(CH₂CH₂O)_(n1)-(cycloalkyl)-O-(heteroaryl)-O—CH₂—,—NR⁶¹(CH₂CH₂O)_(n1)-(cycloalkyl)-O-Aryl-O—CH₂—,—NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-NH-Aryl-O— CH₂—,—NR⁶(CH₂CH₂O)_(n1)-(lower alkyl)-O-Aryl-CH₂,—NR⁶¹(CH₂CH₂O)_(n1)-cycloalkyl-O-Aryl-,—NR⁶¹(CH₂CH₂O)_(n1)-cycloalkyl-O-heteroaryl-,—NR⁶¹(CH₂CH₂)_(n1)-(cycloalkyl)-O-(heterocycle)-CH₂,—NR⁶¹(CH₂CH₂)_(n1)-(heterocycle)-(heterocycle)-CH₂, and—NR⁶¹-(heterocycle)-CH₂;

wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; andR⁶¹ is H, methyl, or ethyl.

In additional embodiments, the Linker is selected from:—N(R⁶¹)—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—,—O—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—,—O—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—O—;—N(R⁶¹)—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—O—;—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—O—;—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—;—O(CH₂)_(m1)O(CH₂)_(n2)O(CH₂)_(p1)O(CH₂)_(q1)OCH₂—;—O(CH₂)_(m1)O(CH₂)_(n2)O(CH₂)_(p1)O(CH₂)_(q1)OCH₂—; wherein

m1, n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5; andR⁶¹ is H, methyl, or ethyl.

In additional embodiments, the Linker is selected from:

m 1, n2, o 1, p 1, q2, and r 1 are independently 1, 2, 3, 4, or 5.

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

wherein R⁷¹ is —O—, —NH, Nalkyl, heteroaliphatic, aliphatic or —NMe.

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In certain embodiments, the Linker is selected from:

In certain embodiments the Linker is selected from:

In the above structures

represents

In certain embodiments, Linker can be a 4-24 carbon atom linear chains,wherein one or more the carbon atoms in the linear chain can be replacedor substituted with oxygen, nitrogen, amide, fluorinated carbon, etc.,such as the following.

In certain embodiments, Linker can be a nonlinear chain, and can be, orinclude, aliphatic or aromatic or heteroaromatic cyclic moieties.

In certain embodiments, the Linker may include contiguous, partiallycontiguous or non-contiguous ethylene glycol unit groups ranging in sizefrom about 1 to about 12 ethylene glycol units, between 1 and about 10ethylene glycol units, about 2 about 6 ethylene glycol units, betweenabout 2 and 5 ethylene glycol units, between about 2 and 4 ethyleneglycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12ethylene glycol units.

In certain embodiments, the Linker may have 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 fluorine substituents. In another embodimentthe Linker is perfluorinated. In yet another embodiment the Linker is apartially or fully fluorinated poly ether. Nonlimiting examples offluorinated Linkers include:

In certain embodiments, where the Target Ligand binds more than oneprotein (i.e., is not completely selective), selectivity may be enhancedby varying Linker length where the ligand binds some of its targets indifferent binding pockets, e.g., deeper or shallower binding pocketsthan others. Therefore, the length can be adjusted as desired.

In certain embodiments, the present application provides Degron-Linker(DL) having the following structure:

In an alternative embodiment, the present application providesDegron-Linker (DL) having the following structure:

wherein each of the variables is as described above in Formula I,Formula II, Formula III, and Formula LI; and

a Targeting Ligand is covalently bonded to the DL through the

next to X².

Target Proteins

Degradation of cellular proteins is required for cell homeostasis andnormal cell function, such as proliferation, differentiation and celldeath. When this system becomes dysfunctional or does not identify andabate abnormal protein behavior in vivo, a disease state can arise in ahost, such as a human. A large range of proteins can cause, modulate oramplify diseases in vivo, as well known to those skilled in the art,published in literature and patent filings as well as presented inscientific presentations.

Therefore, in one embodiment, a selected Degronimer of the presentinvention can be administered in vivo in an effective amount to a hostin need thereof to degrade a selected protein that mediates a disorderto be treated. The selected Target Protein may modulate a disorder in ahuman via a mechanism of action such as modification of a biologicalpathway, pathogenic signaling or modulation of a signal cascade orcellular entry. In one embodiment, the Target Protein is a protein thatis not druggable in the classic sense in that it does not have a bindingpocket or an active site that can be inhibited or otherwise bound, andcannot be easily allosterically controlled. In another embodiment, theTarget Protein is a protein that is druggable in the classic sense, yetfor therapeutic purposes, degradation of the protein is preferred toinhibition.

The Target Protein is recruited with a Targeting Ligand for the TargetProtein. Typically the Degron binds the Target Protein in a non-covalentfashion. In an alternative embodiment, the Target Protein is covalentlybound to the Degron in a manner that can be irreversible or reversible.

In one embodiment, the selected Target Protein is expressed from a genethat has undergone an amplification, translocation, deletion, orinversion event which causes or is caused by a medical disorder. Incertain aspects, the selected Target Protein has beenpost-translationally modified by one, or a combination, ofphosphorylation, acetylation, acylation including propionylation andcrotylation, N-linked glycosylation, amidation, hydroxylation,methylation and poly-methylation, O-linked glycosylation,pyrogultamoylation, myristoylation, farnesylation, geranylgeranylation,ubiquitination, sumoylation, or sulfation which causes or is caused by amedical disorder.

As contemplated herein, the present invention includes an Degronimerwith a Targeting Ligand that binds to a Target Protein of interest. TheTarget Protein is any amino acid sequence to which an Degronimer can bebound which by degradation thereof, causes a beneficial therapeuticeffect in vivo. In one embodiment, the Target Protein is anon-endogenous peptide such as that from a pathogen or toxin. In anotherembodiment, the Target Protein can be an endogenous protein thatmediates a disorder. The endogenous protein can be either the normalform of the protein or an aberrant form. For example, the Target Proteincan be a mutant protein found in cancer cells, or a protein, forexample, where a partial, or full, gain-of-function or loss-of-functionis encoded by nucleotide polymorphisms. In some embodiments, theDegronimer targets the aberrant form of the protein and not the normalform of the protein. In another embodiment, the Target Protein canmediate an inflammatory disorder or an immune disorder, including anauto-immune disorder.

In one embodiment, the Target Protein is a non-endogenous protein from avirus, as non-limiting examples, HIV, HBV, HCV, RSV, HPV, CMV,flavivirus, pestivirus, coronavirus, noroviridae, etc. In oneembodiment, the Target Protein is a non-endogenous protein from abacteria, which may be for example, a gram positive bacteria, gramnegative bacteria or other, and can be a drug-resistant form ofbacteria. In one embodiment, the Target Protein is a non-endogenousprotein from a fungus. In one embodiment, the Target Protein is anon-endogenous protein from a prion. In one embodiment, the TargetProtein is a protein derived from a eukaryotic pathogen, for example aprotist, helminth, etc.

In one aspect, the Target Protein mediates chromatin structure andfunction. The Target Protein may mediate an epigenetic action such asDNA methylation or covalent modification of histones. An example ishistone deacetylase (HDAC 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11).Alternatively, the Target Protein may be a bromodomain, which arereaders of lysine acetylation (for example, BRD1, 2, 3, 4, 5, 6, 7, 8, 9and T. FIG. 9 is a dendogram of the proteins of the bromodomain family,which, for example, can act as Target Proteins according to the presentinvention.

Other nonlimiting examples of Target Proteins are a structural protein,receptor, enzyme, cell surface protein, a protein involved in apoptoticsignaling, aromatase, helicase, mediator of a metabolic process(anabolism or catabolism), antioxidant, protease, kinase,oxidoreductase, transferase, hydrolase, lyase, isomerase, ligase, enzymeregulator, signal transducer, structural molecule, binding activity(protein, lipid carbohydrate), cell motility protein, membrane fusionprotein, cell communication mediator, regulator of biological processes,behavioral protein, cell adhesion protein, protein involved in celldeath, protein involved in transport (including protein transporteractivity, nuclear transport, ion transporter, channel transporter,carrier activity, permease, secretase or secretion mediator, electrontransporter, chaperone regulator, nucleic acid binding, transcriptionregulator, extracellular organization and biogenesis regulator, andtranslation regulator).

In one embodiment, the Target Protein is a modulator of a signalingcascade related to a known disease state. In another embodiment, theTarget Protein mediates a disorder by a mechanism different frommodulating a signaling cascade. Any protein in a eukaryotic system or amicrobial system, including a virus, bacteria or fungus, as otherwisedescribed herein, are targets for proteasomal degradation using thepresent invention. The Target Protein may be a eukaryotic protein, andin some embodiments, a human protein.

In one embodiment, the Target Protein is RXR, DHFR, Hsp90, a kinase,HDM2, MDM2, BET bromodomain-containing protein, HDAC, IDH1, Mcl-1, humanlysine methyltransferase, a nuclear hormone receptor, aryl hydrocarbonreceptor (AHR), RAS, RAF, FLT, SMARC, KSR, NF2L, CTNB, CBLB, BCL.

In one embodiment, a bromodomain containing protein has histone acetyltransferase activity.

In one embodiment, the bromodomain containing protein is BRD2, BRD3,BRD4, BRDT or ASH1L.

In one embodiment, the bromodomain containing protein is a non-BETprotein.

In one embodiment, the non-BET protein is BRD7 or BRD9.

In one embodiment, the FLT is not FLT 3. In one embodiment, the RAS isnot RASK. In one embodiment, the RAF is not RAF1. In one embodiment, theSMARC is not SMARC2. In one embodiment, the KSR is not KSR1. In oneembodiment, the NF2L is not NF2L2. In one embodiment, the CTNB is notCTNB1. In one embodiment, the BCL is not BCL6.

In one embodiment, the Target Protein is selected from: EGFR, FLT3,RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

In another embodiment, the Target Protein is not selected from: EGFR,FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

In one embodiment, the Targeting Ligand is an EGFR ligand, a FLT3ligand, a RAF1 ligand, a SMRCA2 ligand, a KSR1 ligand, a NF2L2 ligand, aCTNB1 ligand, a CBLB ligand, a BCL6 ligand, or a RASK ligand.

In one embodiment, the Targeting Ligand is not a EGFR ligand, a FLT3ligand, a RAF1 ligand, a SMRCA2 ligand, a KSR1 ligand, a NF2L2 ligand, aCTNB1 ligand, a CBLB ligand, a BCL6 ligand, or a RASK ligand.

The present invention may be used to treat a wide range of diseasestates and/or conditions, including any disease state and/or conditionin which a protein is dysregulated and where a patient would benefitfrom the degradation of proteins.

For example, a Target Protein can be selected that is a known target fora human therapeutic, and the therapeutic can be used as the TargetingLigand when incorporated into the Degronimer according to the presentinvention. These include proteins which may be used to restore functionin a polygenic disease, including for example B7.1 and B7, TINFR1m,TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosispathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type,PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclaseinhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1,cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, e.g.,Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease,thymidylate synthase, purine nucleoside phosphorylase, GAPDHtrypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokinereceptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase,influenza, neuraminidase, hepatitis B reverse transcriptase, sodiumchannel, multi drug resistance (MDR), protein P-glycoprotein (and MRP),tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4integrin, selectins, CD40/CD40L, neurokinins and receptors, inosinemonophosphate dehydrogenase, p38 MAP Kinase, Ras/Raf/MER/ERK pathway,interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNAhelicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3Cprotease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus(CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases,vascular endothelial growth factor, oxytocin receptor, microsomaltransfer protein inhibitor, bile acid transport inhibitor, 5 alphareductase inhibitors, angiotensin 11, glycine receptor, noradrenalinereuptake receptor, endothelin receptors, neuropeptide Y and receptor,estrogen receptors, androgen receptors, adenosine receptors, adenosinekinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6,P2×1-7), farnesyltransferases, geranylgeranyl transferase, TrkA areceptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectinreceptor, integrin receptor, Her-2/neu, telomerase inhibition, cytosolicphospholipaseA2 and EGF receptor tyrosine kinase. Additional proteintargets include, for example, ecdysone 20-monooxygenase, ion channel ofthe GABA gated chloride channel, acetylcholinesterase, voltage-sensitivesodium channel protein, calcium release channel, and chloride channels.Still further Target Proteins include Acetyl-CoA carboxylase,adenylosuccinate synthetase, protoporphyrinogen oxidase, andenolpyruvylshikimate-phosphate synthase.

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to, a tyrosine kinase (e.g., AATK, ABL, ABL2, ALK, AXL, BLK,BMX, BTK, CSF1R, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4,EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6,ERBB2, ERBB3, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1,FLT3, FLT4, FRK, FYN, GSG2, HCK, IGF1R, ILK, INSR, INSRR, IRAK4, ITK,JAK1, JAK2, JAK3, KDR, KIT, KSR1, LCK, LMTK2, LMTK3, LTK, LYN, MATK,MERTK, MET, MLTK, MST1R, MUSK, NPR1, NTRK1, NTRK2, NTRK3, PDGFRA,PDGFRB, PLK4, PTK2, PTK2B, PTK6, PTK7, RET, ROR1, ROR2, ROS1, RYK,SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TIEl, TNK1, TNK2,TNNI3K, TXK, TYK2, TYRO3, YES1, or ZAP70).

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to, a serine/threonine kinase (e.g., casein kinase 2,protein kinase A, protein kinase B, protein kinase C, Raf kinases, CaMkinases, AKT1, AKT2, AKT3, ALK1, ALK2, ALK3, ALK4, Aurora A, Aurora B,Aurora C, CHK1, CHK2, CLK1, CLK2, CLK3, DAPK1, DAPK2, DAPK3, DMPK, ERK1,ERK2, ERK5, GCK, GSK3, HIPK, KHS1, LKB1, LOK, MAPKAPK2, MAPKAPK, MNK1,MSSK1, MST1, MST2, MST4, NDR, NEK2, NEK3, NEK6, NEK7, NEK9, NEK11, PAK1,PAK2, PAK3, PAK4, PAK5, PAK6, PIM1, PIM2, PLK1, RIP2, RIP5, RSK1, RSK2,SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TGF-beta, TLK2, TSSK1, TSSK2, ULK1,or ULK2).

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to a cyclin dependent kinase for example CDK1, CDK2, CDK3,CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13.

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to a leucine-rich repeat kinase (e.g., LRRK2).

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to a lipid kinase (e.g., PIK3CA, PIK3CB) or a sphingosinekinase (e.g. S1P).

In certain embodiments, the Target Protein is derived from a BETbromodomain-containing protein to which the Targeting Ligand is capableof binding or binds including, but not limited to, ASH1L, ATAD2, BAZ1A,BAZ1B, BAZ2A, BAZ2B, BRD1, BRD2, BRD3, BRD4, BRD5, BRD6, BRD7, BRD8,BRD9, BRD10, BRDT, BRPF1, BRPF3, BRWD3, CECR2, CREBBP, EP300, FALZ,GCN5L2, KIAA1240, LOC93349, MLL, PB1, PCAF, PHIP, PRKCBP1, SMARCA2,SMARCA4, SP100, SP110, SP140, TAF1, TAF1L, TIF1a, TRIM28, TRIM33,TRIM66, WDR9, ZMYND11, and MLL4. In certain embodiments, a BETbromodomain-containing protein is BRD4.

In certain embodiments, the Target Protein is derived from a nuclearprotein to which the Targeting Ligand is capable of binding or bindsincluding, but not limited to, BRD2, BRD3, BRD4, AntennapediaHomeodomain Protein, BRCA1, BRCA2, CCAAT-Enhanced-Binding Proteins,histones, Polycomb-group proteins, High Mobility Group Proteins,Telomere Binding Proteins, FANCA, FANCD2, FANCE, FANCF, hepatocytenuclear factors, Mad2, NF-kappa B, Nuclear Receptor Coactivators,CREB-binding protein, p55, p107, p130, Rb proteins, p53, c-fos, c-jun,c-mdm2, c-myc, and c-rel.

In one embodiment, the Target Protein is a protein, or a precursor,variant (e.g., a splice variant), mutant (e.g., substitution, deletion,duplication, insertion, insertion/deletion, extension, etc.), homolog,chimeric. polymorph, isoform, modification (e.g., post-translationallymodified through glycosylation, phosphorylation, proteolysis, etc.), orrecombinant thereof.

In certain embodiments, the Target Protein is a member of the Retinoid XReceptor (RXR) family and the disorder treated is a neuropsychiatric orneurodegenerative disorder. In certain embodiments, the Target Proteinis a member of the Retinoid X Receptor (RXR) family and the disordertreated is schizophrenia.

In certain embodiments, the Target Protein is dihydrofolate reductase(DHFR) and the disorder treated is cancer. In certain embodiments, theTarget Protein is dihydrofolate reductase (DHFR) and the disordertreated is microbial.

In certain embodiments, the Target Protein is dihydrofolate reductasefrom Bacillus anthracis (BaDHFR) and the disorder treated is anthrax.

In certain embodiments, the Target Protein is Heat Shock Protein 90(HSP90) and the disorder treated is cancer.

In certain embodiments, the Target Protein is a kinase or phosphataseand the disorder treated is cancer.

In certain embodiments, the Target Protein is HDM2 and or MDM2 and thedisorder treated is cancer.

In certain embodiments, the Target Protein is a BET bromodomaincontaining protein and the disorder treated is cancer.

In certain embodiments, the Target Protein is a lysine methyltransferaseand the disorder treated is cancer.

In certain embodiments, the Target Protein belongs to the RAF family andthe disorder treated is cancer.

In certain embodiments, the Target Protein belongs to the FKBP familyand the disorder treated is an autoimmune disorder. In certainembodiments, the Target Protein belongs to the FKBP family and thedisorder treated is organ rejection. In certain embodiments, the TargetProtein belongs to the FKBP family and the compound is givenprophylactically to prevent organ failure.

In certain embodiments, the Target Protein is an androgen receptor andthe disorder treated is cancer.

In certain embodiments, the Target Protein is an estrogen receptor andthe disorder treated is cancer.

In certain embodiments, the Target Protein is a viral protein and thedisorder treated is a viral infection. In certain embodiments, theTarget Protein is a viral protein and the disorder treated is HIV, HPV,or HCV.

In certain embodiments, the Target Protein is an AP-1 or AP-2transcription factor and the disorder treated is cancer.

In certain embodiments, the Target Protein is a HIV protease and thedisorder treated is a HIV infection. In certain embodiments, the TargetProtein is a HIV integrase and the disorder treated is a HIV infection.In certain embodiments, the Target Protein is a HCV protease and thedisorder treated is a HCV infection. In certain embodiments, thetreatment is prophylactic and the Target Protein is a viral protein.

In certain embodiments, the Target Protein is a member of the histonedeacetylase (HDAC) family and the disorder is a neurodegenerativedisorder. In certain embodiments, the Target Protein is a member of thehistone deacetylase (HDAC) family and the disorder is Huntingon's,Parkinson's, Kennedy disease, amyotropic lateral sclerosis,Rubinstein-Taybi syndrome, or stroke.

In certain embodiments, the Target Protein as referred to herein isnamed by the gene that expresses it. The person skilled in the art willrecognize that when a gene is referred to as a Target Protein, theprotein encoded by the gene is the Target Protein. For example, ligandsfor the protein SMCA2 which is encoded by SMRCA2 are referred to asSMRCA2 Targeting Ligands.

FIG. 9 is a dendrogram of the human bromodomain family of proteinsorganized into eight subfamilies, which are involved in epigeneticsignaling and chromatin biology. Any of the proteins of the bromodomainfamily in FIG. 9 can be selected as a Target Protein according to thepresent invention.

Targeting Ligands

In certain aspects, the Targeting Ligand is a ligand which covalently ornon-covalently binds to a Target Protein which has been selected forproteasomal degradation by the selected Degronimer. FIGS. 1A-8JJJJJdescribe targeting ligands for a number of proteins wherein R is thepoint of attachment for the linker. While specific targeting ligands areexemplified in the figures, additional ligands and examples can be foundin the references cited in the brief description of figures or aregenerally known in the art.

In one embodiment, the Targeting Ligand binds to an endogenous proteinwhich has been selected for degradation as a means to achieve atherapeutic effect on the host. Illustrative Targeting Ligands include:RXR ligands, DHFR ligands, Hsp90 inhibitors, kinase inhibitors, HDM2 andMDM2 inhibitors, compounds targeting Human BET bromodomain-containingproteins, HDAC inhibitors, ligands of MerTK, ligands of IDH1, ligands ofMcl-1,ligands of SMRCA2, ligands of EGFR, ligands of RAF, ligands ofcRAF, human lysine methyltransferase inhibitors, angiogenesisinhibitors, nuclear hormone receptor compounds, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR),among numerous others. Targeting Ligands also considered to includetheir pharmaceutically acceptable salts, prodrugs and isotopicderivatives.

In certain aspects, the Targeting Ligand binds to a dehalogenase enzymein a patient or subject or in a diagnostic assay and is a haloalkane(preferably a C₁-C₁₀ alkyl group which is substituted with at least onehalo group, preferably a halo group at the distal end of the alkyl group(i.e., away from the Linker). In still other embodiments, the TargetingLigand is a haloalkyl group, wherein said alkyl group generally rangesin size from about 1 or 2 carbons to about 12 carbons in length, oftenabout 2 to 10 carbons in length, often about 3 carbons to about 8carbons in length, more often about 4 carbons to about 6 carbons inlength. The haloalkyl groups are generally linear alkyl groups (althoughbranched-chain alkyl groups may also be used) and are end-capped with atleast one halogen group, preferably a single halogen group, often asingle chloride group. Haloalkyl PT, groups for use in the presentinvention are preferably represented by the chemical structure(CH₂)_(v)-Halo where v is any integer from 2 to about 12, often about 3to about 8, more often about 4 to about 6. Halo may be any halogen, butis preferably Cl or Br, more often Cl.

In certain embodiments, the Targeting Ligand is a retinoid X receptor(RXR) agonist or antagonist. Non-limiting examples include retinol,retinoic acid, bexarotene, docosahexenoic acid, compounds disclosed inWO 9929324, the publication by Canan Koch et al. (J. Med. Chem. 1996,39, 3229-3234) titled “Identification of the First Retinoid X ReceptorHomodimer Antagonist”, WO 9712853, EP 0947496A1, WO 2016002968, andanalogs thereof.

In certain embodiments, the Targeting Ligand is a DHFR agonist orantagonist. Non-limiting examples include folic acid, methotrexate,8,10-dideazatetrahydrofolate compounds disclosed by Tian et al. (Chem.Biol. Drug Des. 2016, 87, 444-454) titled “Synthesis, Antifolate andAnticancer Activities of N5-Substituted 8,10-DideazatetrahydrofolateAnalogues”, compounds prepared by Kaur et al. (Biorg. Med. Chem. Lett.2016, 26, 1936-1940) titled “Rational Modification of the Lead Molecule:Enhancement in the Anticancer and Dihydrofolate Reductase InhibitoryActivity”, WO 2016022890, compounds disclosed by Zhang et al. (Int. J.Antimicrob. Agents 46, 174-182) titled “New Small-Molecule Inhibitors ofDihydrofolate Reductase Inhibit Streptococcus Mutans”, modifiedtrimethoprim analogs developed by Singh et al. (J. Med. Chem. 2012, 55,6381-6390) titled “Mechanism Inspired Development of Rationally DesignedDihydrofolate Reductase Inhibitors as Anticancer Agents”, WO20111153310,and analogs thereof.

In certain embodiments, the Targeting Ligand derived from estrogen, anestrogen analog, SERM (selective estrogen receptor modulator), a SERD(selective estrogen receptor degrader), a complete estrogen receptordegrader, or another form of partial or complete estrogen antagonist oragonist. Examples are the partial anti-estrogens raloxifene andtamoxifen and the complete antiestrogen fulvestrant. Non-limitingexamples of anti-estrogen compounds are provided in WO 2014/19176assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO 2014/203132,and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Pat. Nos.9,078,871, 8,853,423, and 8,703,810, as well as US 2015/0005286, WO2014/205136, and WO 2014/205138. Additional non-limiting examples ofanti-estrogen compounds include: SERMS such as anordrin, bazedoxifene,broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil,lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, andfulvestrant; aromatase inhibitors such as aminoglutethimide,testolactone, anastrozole, exemestane, fadrozole, formestane, andletrozole; and antigonadotropins such as leuprorelin, cetrorelix,allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinoneacetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate,nomegestrol acetate, norethisterone acetate, progesterone, andspironolactone. Other estrogenic ligands that can be used according tothe present invention are described in U.S. Pat. Nos. 4,418,068;5,478,847; 5,393,763; and 5,457,117, WO2011/156518, U.S. Pat. Nos.8,455,534 and 8,299,112, 9,078,871; 8,853,423; 8,703,810; US2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO2014/191726, WO 2012/084711; WO 2002/013802; WO 2002/004418; WO2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO2002/003975; WO 2006/078834; U.S. Pat. No. 6,821,989; US 2002/0128276;U.S. Pat. No. 6,777,424; US 2002/0016340; U.S. Pat. Nos. 6,326,392;6,756,401; US 2002/0013327; U.S. Pat. Nos. 6,512,002; 6,632,834; US2001/0056099; U.S. Pat. Nos. 6,583,170; 6,479,535; WO 1999/024027; U.S.Pat. No. 6,005,102; EP 0802184; U.S. Pat. Nos. 5,998,402; 5,780,497,5,880,137, WO 2012/048058 and WO 2007/087684.

In certain embodiments, the Targeting Ligand is a HSP90 inhibitoridentified in Vallee et al. (J. Med. Chem. 2011, 54, 7206-7219) titled“Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I:Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors ofthe Hsp90 Molecular Chaperone”, including YKB(N-[4-(3H-imidazo[4,5-C]Pyridin-2-yl)-9H-Fluoren-9-yl]-succinamide), aHSP90 inhibitors (modified) identified in Brough et al. (J. Med. Chem.2008, 51, 196-218) titled “4,5-Diarylisoxazole Hsp90 ChaperoneInhibitors: Potential Therapeutic Agents for the Treatment of Cancer”,including compound 2GJ(5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide),the HSP90 inhibitor geldanamycin((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1](derivatized) or any of its derivatives (e.g.17-alkylamino-17-desmethoxygeldanamycin (“17-AAG”) or17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin (“17-DMAG”)),or a HSP90 inhibitor (modified) identified in Wright et al. (Chem. Biol.2004, 11, 775-785) titled “Structure-Activity Relationships inPurine-Based Inhibitor Binding to Hsp90 Isoforms”, including the HSP90inhibitor PU3. Other non-limiting examples of Hsp90 Targeting Ligandsinclude SNX5422 currently in phase I clinical trials Reddy et al. (Clin.Lymphoma Myeloma Leuk. 2013, 13, 385-391) titled “Phase I Trial of theHsp90 Inhibitor Pf-04929113 (Snx5422) in Adult Patients with Recurrent,Refractory Hematologic Malignancies”, or NVP-AUY922 whose anti-canceractivity was assessed by Jensen et al. (Breast Cancer Research: BCR2008, 10, R33-R³³) titled “Nvp-Auy922: A Small Molecule Hsp90 Inhibitorwith Potent Antitumor Activity in Preclinical Breast Cancer Models”.

In certain embodiments, the Targeting Ligand is a kinase inhibitoridentified in Millan et al. (J. Med Chem. 2011, 54, 7797-7814) titled“Design and Synthesis of Inhaled P38 Inhibitors for the Treatment ofChronic Obstructive Pulmonary Disease”, including the kinase inhibitorsY1W and Y1X, a kinase inhibitor identified in Schenkel et al. (J. MedChem. 2011, 54, 8440-8450) titled “Discovery of Potent and HighlySelective Thienopyridine Janus Kinase 2 Inhibitors”, including thecompounds 6TP and OTP, a kinase inhibitor identified in van Eis et al.(Biorg. Med Chem. Lett. 2011, 21, 7367-7372) titled “2,6-Naphthyridinesas Potent and Selective Inhibitors of the Novel Protein Kinase CIsozymes”, including the kinase inhibitors 07U and YCF identified inLountos et al. (J. Struct. Biol. 2011, 176, 292-301) titled “StructuralCharacterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2),a Drug Target for Cancer Therapy”, including the kinase inhibitors XK9and NXP, afatinib, fostamatinib, gefitinib, lenvatinib, vandetanib,Gleevec, pazopanib, AT-9283, TAE684, nilotanib, NVP-BSK805, crizotinib,JNJ FMS, foretinib, OSI-027, OSI-930, or OSI-906.

In certain embodiments, the Targeting Ligand is a HDM2/MDM2 inhibitoridentified in Vassilev et al. (Science 2004, 303, 844-848) titled “InVivo Activation of the P53 Pathway by Small-Molecule Antagonists ofMdm2”, and Schneekloth et al. (Bioorg. Med Chem. Lett. 2008, 18,5904-5908) titled “Targeted Intracellular Protein Degradation Induced bya Small Molecule: En Route to Chemical Proteomics”, including thecompounds nutlin-3, nutlin-2, and nutlin-1.

In certain embodiments, the Targeting Ligand is a Human BET BromodomainTargeting Ligand identified in Filippakopoulos et al. (Nature 2010, 468,1067-1073) titled “Selective Inhibition of Bet Bromodomains” such asJQ1; a ligand identified in Nicodeme et al. (Nature 2010, 468,1119-1123) titled “Suppression of Inflammation by a Synthetic HistoneMimic”; Chung et al. (J. Med Chem. 2011, 54, 3827-3838) titled“Discovery and Characterization of Small Molecule Inhibitors of the BetFamily Bromodomains”; a compound disclosed in Hewings et al. (J. MedChem. 2011, 54, 6761-6770) titled “3,5-Dimethylisoxazoles Act asAcetyl-Lysine-Mimetic Bromodomain Ligands”; a ligand identified inDawson et al. (Nature 2011, 478, 529-533) titled “Inhibition of BetRecruitment to Chromatin as an Effective Treatment for MLL-FusionLeukaemia”; or a ligand identified in the following patent applicationsUS 2015/0256700, US 2015/0148342, WO 2015/074064, WO 2015/067770, WO2015/022332, WO 2015/015318, and WO 2015/011084.

In certain embodiments, the Targeting Ligand is a HDAC Targeting Ligandidentified in Finnin et al. (Nature 1999, 401, 188-193) titled“Structures of a Histone Deacetylase Homologue Bound to the Tsa and SahaInhibitors”, or a ligand identified as Formula (I) in PCT WO0222577.

In certain embodiments, the Targeting Ligand is a Human LysineMethyltransferase ligand identified in Chang et al. (Nat Struct Mol Biol2009, 16, 312-317) titled “Structural Basis for G9a-Like Protein LysineMethyltransferase Inhibition by Bix-01294”, a ligand identified in Liuet al. (J Med Chem 2009, 52, 7950-7953) titled “Discovery of a2,4-Diamino-7-Aminoalkoxyquinazoline as a Potent and Selective Inhibitorof Histone Lysine Methyltransferase G9a”, azacitidine, decitabine, or ananalog thereof.

In certain embodiments, the Targeting Ligand is an angiogenesisinhibitor. Non-limiting examples of angiogenesis inhibitors include:GA-1, estradiol, testosterone, ovalicin, fumagillin, and analogsthereof.

In certain embodiments, the Targeting Ligand is an immunosuppressivecompound. Non-limiting examples of immunosuppressive compounds include:AP21998, hydrocortisone, prednisone, prednisolone, methylprednisolone,beclometasone dipropionate, methotrexate, ciclosporin, tacrolimus,actinomycin, and analogues thereof.

In certain embodiments, the Targeting Ligand is an Aryl HydrocarbonReceptor (AHR) ligand. Non-limiting examples of AHR ligands include:apigenin, SR1, LGC006, and analogues thereof.

In certain embodiments, the Targeting Ligand is a MerTK or Mer Targetingligand. Non-limiting examples of MerTK Targeting Ligands are included inWO2013/177168 and WO2014/085225, both titled “Pyrimidine Compounds forthe Treatment of Cancer” filed by Wang, et al.

In certain embodiments, the Targeting Ligand is an EGFR ligand. Incertain embodiments the Targeting Ligand is an EGRF ligand selected fromAfatinib, Dacomitinib, Neratinib, Poziotinib, and Canertinib, orderivatives thereof.

In certain embodiments, the Targeting Ligand is a FLT3 Ligand. Incertain embodiments, the Targeting Ligand is a FLT3 ligand selected fromTandutinib, Lestaurtinib, Sorafenib, Midostaurin, Quizartinib, andCrenolanib.

In certain embodiments, the Targeting Ligand is a RAF inhibitor. Incertain embodiments the Targeting Ligand is a RAF inhibitor selectedfrom Dabrafenib, Regorafenib, and Vemurafenib.

In certain embodiments the Targeting Ligand is a cRAF inhibitor.

In some embodiments, the Targeting Ligand is an Ubc9 SUMO E2 ligase 5F6DTargeting Ligand including but not limited to those described in“Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.” byHewitt, W. M., et. al. (2016) Angew.Chem.Int.Ed.Engl. 55: 5703-5707

In another embodiment, the Targeting Ligand is a Tank1 Targeting Ligandincluding but not limited to those described in “Structure of humantankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939.”Kirby, C. A., Cheung, A., Fazal, A., Shultz, M.D., Stams, T, (2012) ActaCrystallogr., Sect. F 68: 115-118; and “Structure-EfficiencyRelationship of [1,2,4]Triazol-3-ylamines as Novel NicotinamideIsosteres that Inhibit Tankyrases.” Shultz, M. D., et al. (2013)J.Med.Chem. 56: 7049-7059.

In another embodiment, the Targeting Ligand is a SH2 domain of pp60 SrcTargeting Ligand including but not limited to those described in“Requirements for Specific Binding of Low Affinity Inhibitor Fragmentsto the SH2 Domain of pp60Src Are Identical to Those for High AffinityBinding of Full Length Inhibitors,” Gudrun Lange, et al., J. Med. Chem.2003, 46, 5184-5195.

In another embodiment, the Targeting Ligand is a Sec7 domain TargetingLigand including but not limited to those described in “The LysosomalProtein Saposin B Binds Chloroquine,” Huta, B. P., et al., (2016)Chemmedchem 11: 277.

In another embodiment, the Targeting Ligand is a Saposin-B TargetingLigand including but not limited to those described in “The structure ofcytomegalovirus immune modulator UL141 highlights structural Ig-foldversatility for receptor binding” I. Nemcovicova and D. M. Zajonc ActaCryst. (2014). D70, 851-862.

In another embodiment, the Targeting Ligand is a Protein S100-A7 20WSTargeting Ligand including but not limited to those described in “2WOSSTRUCTURE OF HUMAN S100A7 IN COMPLEX WITH 2,6 ANS” DOI:10.2210/pdb2wos/pdb; and “Identification and Characterization of BindingSites on S100A7, a Participant in Cancer and Inflammation Pathways.”Leon, R., Murray, et al., (2009) Biochemistry 48: 10591-10600.

In another embodiment, the Targeting Ligand is a Phospholipase A2Targeting Ligand including but not limited to those described in“Structure-based design of the first potent and selective inhibitor ofhuman non-pancreatic secretory phospholipase A2” Schevitz, R. W., etal., Nat. Struct. Biol. 1995, 2, 458-465.

In another embodiment, the Targeting Ligand is a PHIP Targeting Ligandincluding but not limited to those described in “A Poised FragmentLibrary Enables Rapid Synthetic Expansion Yielding the First ReportedInhibitors of PHIP(2), an Atypical Bromodomain” Krojer, T.; et al. Chem.Sci. 2016, 7, 2322-2330.

In another embodiment, the Targeting Ligand is a PDZ Targeting Ligandincluding but not limited to those described in “Discovery ofLow-Molecular-Weight Ligands for the AF6 PDZ Domain” Mangesh Joshi, etal. Angew. Chem. Int. Ed. 2006, 45, 3790-3795.

In another embodiment, the Targeting Ligand is a PARP15 Targeting Ligandincluding but not limited to those described in “Structural Basis forLack of ADP-ribosyltransferase Activity in Poly(ADP-ribose)Polymerase-13/Zinc Finger Antiviral Protein.” Karlberg, T., et al.,(2015) J.Biol.Chem. 290: 7336-7344.

In another embodiment, the Targeting Ligand is a PARP14 Targeting Ligandincluding but not limited to those described in “Discovery of Ligandsfor ADP-Ribosyltransferases via Docking-Based Virtual Screening.”Andersson, C. D., et al., (2012) J.Med.Chem. 55: 7706-7718.;“Family-wide chemical profiling and structural analysis of PARP andtankyrase inhibitors.” Wahlberg, E., et al. (2012) Nat.Biotechnol. 30:283-288.; “Discovery of Ligands for ADP-Ribosyltransferases viaDocking-Based Virtual Screening. “Andersson, C. D., et al. (2012)J.Med.Chem. 55: 7706-7718.

In another embodiment, the Targeting Ligand is a MTH1 Targeting Ligandincluding but not limited to those described in “MTH1 inhibitioneradicates cancer by preventing sanitation of the dNTP pool” Helge Gad,et. al. Nature, 2014, 508, 215-221.

In another embodiment, the Targeting Ligand is a mPGES-1 TargetingLigand including but not limited to those described in “CrystalStructures of mPGES-1 Inhibitor Complexes Form a Basis for the RationalDesign of Potent Analgesic and Anti-Inflammatory Therapeutics.” Luz, J.G., et al., (2015) J.Med.Chem. 58: 4727-4737.

In another embodiment, the Targeting Ligand is aFLAP-5-lipoxygenase-activating protein Targeting Ligand including butnot limited to those described in “Crystal structure of inhibitor-boundhuman 5-lipoxygenase-activating protein,” Ferguson, A. D., McKeever, B.M., Xu, S., Wisniewski, D., Miller, D. K., Yamin, T. T., Spencer, R. H.,Chu, L., Ujjainwalla, F., Cunningham, B. R., Evans, J. F., Becker, J. W.(2007) Science 317: 510-512.

In another embodiment, the Targeting Ligand is a FA Binding ProteinTargeting Ligand including but not limited to those described in “AReal-World Perspective on Molecular Design.” Kuhn, B.; et al. J. Med.Chem. 2016, 59, 4087-4102.

In another embodiment, the Targeting Ligand is a BCL2 Targeting Ligandincluding but not limited to those described in “ABT-199, a potent andselective BCL-2 inhibitor, achieves antitumor activity while sparingplatelets.” Souers, A. J., et al. (2013) NAT.MED. (N.Y.) 19: 202-208.

In another embodiment, the Targeting Ligand is a NF2L2 Targeting Ligand.

In another embodiment, the Targeting Ligand is a CTNNB1 TargetingLigand.

In another embodiment, the Targeting Ligand is a CBLB Targeting Ligand.

In another embodiment, the Targeting Ligand is a BCL6 Targeting Ligand.

In another embodiment, the Targeting Ligand is a RASK Targeting Ligand.

In another embodiment, the Targeting Ligand is a TNIK Targeting Ligand.

In another embodiment, the Targeting Ligand is a MEN1 Targeting Ligand.

In another embodiment, the Targeting Ligand is a PI3Ka Targeting Ligand.

In another embodiment, the Targeting Ligand is a IDO1 Targeting Ligand.

In another embodiment, the Targeting Ligand is a MCL1 Targeting Ligand.

In another embodiment, the Targeting Ligand is a PTPN2 Targeting Ligand.

In another embodiment, the Targeting Ligand is a HER2 Targeting Ligand.

In another embodiment, the Targeting Ligand is an EGFR Targeting Ligand.In one embodiment the Targeting Ligand is selected from erlotinib(Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib(CO-1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib(ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib(BPI-2009), neratinib (HKI-272; PB272); avitinib (ACO0010), EAI045,tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib(XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, anddacomitinib (PF-00299804; Pfizer). The linker can be placed on theseTargeting Ligands in any location that does not interfere with theLigands binding to EGFR. Non-limiting examples of Linker bindinglocations are provided in the below tables. In one embodiment, the EGFRTargeting Ligand binds the L858R mutant of EGFR. In another embodiment,the EGFR Targeting Ligand binds the T790M mutant of EGFR. In anotherembodiment, the EGFR Targeting Ligand binds the C797G or C797S mutant ofEGFR. In one embodiment, the EGFR Targeting Ligand is selected fromerlotinib, gefitinib, afatinib, neratinib, and dacomitinib and binds theL858R mutant of EGFR. In another embodiment, the EGFR Targeting Ligandis selected from osimertinib, rociletinib, olmutinib, naquotinib,nazartinib, PF-06747775, Icotinib, Neratinib, Avitinib, Tarloxotinib,PF-0645998, Tesevatinib, Transtinib, WZ-3146, WZ8040, and CNX-2006 andbinds the T790M mutant of EGFR. In another embodiment, the EGFRTargeting Ligand is EAI045 and binds the C797G or C797S mutant of EGFR.

In one embodiment, the protein target and Targeting Ligand pair arechosen by screening a library of ligands. Such a screening isexemplified in “Kinase Inhibitor Profiling Reveals UnexpectedOpportunities to Inhibit Disease-Associated Mutant Kinases” by Duong-Lyet al.; Cell Reports 14, 772-781 Feb. 2, 2016.

In one embodiment, the protein target and Targeting Ligand pair arediscovered by screening promiscuous kinase binding ligands forcontext-specific degradation. Non-limiting examples of targeting ligandsare shown below and are found in “Optimized Chemical Proteomics Assayfor Kinase Inhibitor Profiling” Guillaume Medard, Fiona Pachl, BenjaminRuprecht, Susan Klaeger, Stephanie Heinzlmeir, Dominic Helm, HuichaoQiao, Xin Ku, Mathias Wilhelm, Thomas Kuehne, Zhixiang Wu, AntjeDittmann, Carsten Hopf, Karl Kramer, and Bernhard Kuster J. ProteomeRes., 2015, 14(3), pp 1574-1586:

These ligands can be attached to linkers as shown below:

wherein:R is the point at which the Linker is attached.

According to the present invention, the Targeting Ligand can becovalently bound to the Linker in any manner that achieves the desiredresults of the Degronimer for therapeutic use. In certain non-limitingembodiments, the Targeting Ligand is bound to the Linker with afunctional group that does not adversely affect the binding of theLigand to the Target Protein. The attachment points below are exemplaryin nature and one of ordinary skill in the art would be able todetermine different appropriate attachment points.

The non-limiting compounds described below exemplify some of the membersof these types of small molecule Targeting Ligands. In the Tables below,R is the point at which the Linker is attached to the Targeting Ligand.

In certain embodiments, the Targeting Ligand is a compound of FormulaTL-I:

or a pharmaceutically acceptable salt thereof, wherein:

is

A¹ is S or C═C;

A² is NRa⁵ or O;

nn1 is 0, 1, or 2;

each Ra¹ is independently C₁-C₃ alkyl, (CH₂)₀₋₃—CN, (CH₂)₀₋₃-halogen,(CH₂)₀₋₃—OH, (CH₂)₀₋₃—C₁-C₃ alkoxy, or R;

Ra² is H, C₁-C₆ alkyl, (CH₂)₀₋₃-heterocyclyl, (CH₂)₀₋₃-phenyl, or R,wherein the heterocyclyl comprises one saturated 5- or 6-membered ringand 1-2 heteroatoms selected from N, O, and S and is optionallysubstituted with C₁-C₃ alkyl and wherein the phenyl is optionallysubstituted with C₁-C₃ alkyl, CN, halogen, OH, C₁-C₃ alkoxy;

nn2 is 0, 1, 2, or 3;

each Ra³ is independently C₁-C₃ alkyl, (CH₂)₀₋₃—CN, (CH₂)₀₋₃-halogen, orR;

Ra⁴ is C₁-C₃ alkyl;

Ra⁵ is H or C₁-C₃ alkyl; and

R is the point at which the Linker is attached.

wherein the compound of Formula TL-I is substituted with only one R.

In certain embodiments, the Targeting Ligand is a compound of FormulaTL-VIII or Formula TL-IX:

wherein the compound of Formula TL-VIII or TL-IX is substituted withonly one R.

In certain embodiments,

In certain embodiments,

In certain embodiments, A¹ is S.

In certain embodiments, A¹ is C═C.

In certain embodiments, A² is NRa⁵. In further embodiments, Ra⁵ is H. Inother embodiments, Ra⁵ is C₁-C₃ alkyl (e.g., methyl, ethyl, propyl, ori-propyl). In further embodiments, Ra⁵ is methyl.

In certain embodiments, A² is O.

In certain embodiments, nn1 is 0.

In certain embodiments, nn1 is 1.

In certain embodiments, nn1 is 2.

In certain embodiments, at least one Ra¹ is C₁-C₃ alkyl (e.g., methyl,ethyl, propyl, or i-propyl). In further embodiments, at least one Ra¹ ismethyl. In further embodiments, two Ra¹ are methyl.

In certain embodiments, at least one Ra¹ is CN, (CH₂)—CN, (CH₂)₂—CN, or(CH₂)₃—CN. In further embodiments, at least one Ra¹ is (CH₂)—CN.

In certain embodiments, at least one Ra¹ is halogen (e.g., F, Cl, orBr), (CH₂)-halogen, (CH₂)₂-halogen, or (CH₂)₃-halogen. In furtherembodiments, at least one Ra¹ is Cl, (CH₂)—Cl, (CH₂)₂—Cl, or (CH₂)₃—Cl.

In certain embodiments, at least one Ra¹ is OH, (CH₂)—OH, (CH₂)₂—OH, or(CH₂)₃—OH.

In certain embodiments, at least one Ra¹ is C₁-C₃ alkoxy (e.g., methoxy,ethoxy, or propoxy), (CH₂)—C₁-C₃ alkoxy, (CH₂)₂—C₁-C₃ alkoxy, or(CH₂)₃—C₁-C₃ alkoxy. In certain embodiments, at least one Ra¹ ismethoxy.

In further embodiments, Ra⁵ is H. In other embodiments, Ra⁵ is C₁-C₃alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

In further embodiments, Ra⁵ is H. In other embodiments, Ra⁵ is C₁-C₃alkyl (e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments,Ra⁵ is methyl.

In certain embodiments, one Ra¹ is R.

In certain embodiments, Ra² is H.

In certain embodiments, Ra² is straight-chain C₁-C₆ or branched C₃-C₆alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl). In further embodiments, Ra² is methyl, ethyl, ort-butyl.

In certain embodiments, Ra² is heterocyclyl, (CH₂)-heterocyclyl,(CH₂)₂-heterocyclyl, or (CH₂)₃-heterocyclyl. In further embodiments, Ra²is (CH₂)₃-heterocyclyl. In further embodiments, the heterocyclyl isselected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazinyl, hexahydropyrimidinyl, morpholinyl, and thiomorpholinyl. Infurther embodiments, the heterocyclyl is piperazinyl.

In certain embodiments, the heterocyclyl is substituted with C₁-C₃ alkyl(e.g., methyl, ethyl, propyl, or i-propyl).

In certain embodiments, Ra² is phenyl, (CH₂)-phenyl, (CH₂)₂-phenyl, or(CH₂)₃-phenyl. In further embodiments, Ra² is phenyl.

In certain embodiments, the phenyl is substituted with C₁-C₃ alkyl(e.g., methyl, ethyl, propyl, or i-propyl). In certain embodiments, thephenyl is substituted with CN. In certain embodiments, the phenyl issubstituted with halogen (e.g., F, Cl, or Br). In certain embodiments,the phenyl is substituted with OH. In certain embodiments, the phenyl issubstituted with C₁-C₃ alkoxy (e.g., methoxy, ethoxy, or propoxy).

In certain embodiments, Ra² is R.

In certain embodiments, nn2 is 0.

In certain embodiments, nn2 is 1.

In certain embodiments, nn2 is 2.

In certain embodiments, nn2 is 3.

In certain embodiments, at least one Ra³ is C₁-C₃ alkyl (e.g., methyl,ethyl, propyl, or i-propyl). In further embodiments, at least one Ra³ ismethyl.

In certain embodiments, at least one Ra³ is CN, (CH₂)—CN, (CH₂)₂—CN, or(CH₂)₃—CN. In further embodiments, at least one Ra³ is CN.

In certain embodiments, at least one Ra³ is halogen (e.g., F, Cl, orBr), (CH₂)-halogen, (CH₂)₂-halogen, or (CH₂)₃-halogen. In furtherembodiments, at least one Ra³ is Cl, (CH₂)—Cl, (CH₂)₂—Cl, or (CH₂)₃—Cl.In further embodiments, at least one Ra³ is Cl.

In certain embodiments, one Ra³ is R.

In further embodiments, Ra⁵ is H. In other embodiments, Ra⁵ is C₁-C₃alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

In certain embodiments, Ra⁴ is C₁-C₃ alkyl (e.g., methyl, ethyl, propyl,or i-propyl). In further embodiments, Ra⁴ is methyl.

In certain embodiments, Ra⁵ is H.

In certain embodiments, Ra⁵ is C₁-C₃ alkyl (e.g., methyl, ethyl, propyl,or i-propyl). In further embodiments, Ra⁵ is methyl.

In certain embodiments,

and A¹ is S.

In certain embodiments,

and A¹ is C═C.

In certain embodiments,

and A¹ is C═C.

In certain embodiments, A² is NH, and Ra² is (CH₂)₀₋₃-heterocyclyl. Infurther embodiments, Ra² is (CH₂)₃-heterocyclyl.

In certain embodiments, A² is NH, and Ra² is (CH₂)₀₋₃-phenyl. In furtherembodiments, Ra² is phenyl. In further embodiments, the phenyl issubstituted with OH.

In certain embodiments, A² is NH, and Ra² is R.

In certain embodiments, A² is NH, and Ra² is H or C₁-C₆ alkyl. Infurther embodiments, Ra² is C₁-C₄ alkyl.

In certain embodiments, A² is O, and Ra² is H or C₁-C₆ alkyl. In furtherembodiments, Ra² is C₁-C₄ alkyl.

III. Methods of Treatment

The compound of Formulas I, II, III, IV, V and VI can be used in aneffective amount to treat a host with any of the disorders describedherein, including a human, in need thereof, optionally in apharmaceutically acceptable carrier. In certain embodiments, the methodcomprises administering an effective amount of the active compound orits salt as described herein, optionally including a pharmaceuticallyacceptable excipient, carrier, adjuvant, i.e., a pharmaceuticallyacceptable composition, optionally in combination or alternation withanother bioactive agent or combination of agents.

The compound of Formula I, II, and III or a pharmaceutically acceptablesalt thereof as described herein can be used to degrade a Target Proteinwhich is a mediator of the disorder affecting the patient, such as ahuman. The reduction in the Target Protein level afforded by the FormulaI, II, or III Degronimers of the present invention provides treatment ofthe implicated disease state or condition, which is modulated throughthe Target Protein by lowering the level of that protein in the cell,e.g., cell of a patient. The term “disease state or condition” when usedin connection with a Formula I, II or III is meant to refer to anydisease state or condition wherein protein dysregulation occurs thatinvolves the selected Target Protein and where degradation of suchprotein in a patient may provide beneficial therapy or relief ofsymptoms to a patient in need thereof. In certain instances, the diseasestate or condition may be cured.

The compounds of Formula I, II or III are useful as therapeutic agentswhen administered in an effective amount to a host, including a human,to treat a tumor, cancer (solid, non-solid, diffuse, hematological,etc), abnormal cellular proliferation, immune disorder, inflammatorydisorder, blood disorder, a myelo- or lymphoproliferative disorder suchas B- or T-cell lymphomas, multiple myeloma, breast cancer, prostatecancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer,skin cancer, melanoma, Waldenstrom's macroglobulinemia, Wiskott-Aldrichsyndrome, or a post-transplant lymphoproliferative disorder; anautoimmune disorder, for example, Lupus, Crohn's Disease, Addisondisease, Celiac disease, dermatomyositis, Graves disease, thyroiditis,multiple sclerosis, pernicious anemia, reactive arthritis, or type Idiabetes; a disease of cardiologic malfunction, includinghypercholesterolemia; an infectious disease, including a viral and/orbacterial infection; an inflammatory condition, including asthma,chronic peptic ulcers, tuberculosis, rheumatoid arthritis,periodontitis, ulcerative colitis, or hepatitis.

The term “disease state or condition” when used in connection with aFormula IV, V and VI, for example, refers to any therapeutic indicationwhich can be treated by decreasing the activity of cereblon or acereblon-containing E3 Ligase, including but not limited to uses knownfor the cereblon binders thalidomide, pomalidomide or lenalidomide. Thecompounds of Formula IV, V or VI can increase, decrease or modify theaction of cereblon via binding. Nonlimiting examples of uses forcereblon binders are multiple myeloma, a hematological disorder such asmyelodysplastic syndrome, cancer, tumor, abnormal cellularproliferation, breast cancer, prostate cancer, AIL, ALL, ACL, lungcancer, pancreatic cancer, colon cancer, skin cancer, melanoma,HIV/AIDS, HBV, HCV, hepatitis, Crohn's disease, sarcoidosis,graft-versus-host disease, rheumatoid arthritis, Behcet's disease,tuberculosis, and myelofibrosis. Other indications include a myelo- orlymphoproliferative disorder such as B- or T-cell lymphomas,Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or apost-transplant lymphoproliferative disorder; an immune disorder,including autoimmune disorders for example as Lupus, Addison disease,Celiac disease, dermatomyositis, Graves disease, thyroiditis, multiplesclerosis, pernicious anemia, arthritis, and in particular rheumatoidarthritis, or type I diabetes; a disease of cardiologic malfunction,including hypercholesterolemia; an infectious disease, including viraland/or bacterial infection, as described generally herein; aninflammatory condition, including asthma, chronic peptic ulcers,tuberculosis, rheumatoid arthritis, periodontitis and ulcerativecolitis.

In certain embodiments, the present invention provides theadministration of an effective amount of a compound to treat a patient,for example, a human, having an infectious disease, wherein the therapytargets a Target Protein of the infectious agent or host (Formulas I,II, III), or acts via binding to cereblon or its E3 ligase (Formulas IV,V or VI) optionally in combination with another bioactive agent. Thedisease state or condition may be caused by a microbial agent or otherexogenous agent such as a virus (as non-limiting examples, HIV, HBV,HCV, HSV, HPV, RSV, CMV, Ebola, Flavivirus, Pestivirus, Rotavirus,Influenza, Coronavirus, EBV, viral pneumonia, drug-resistant viruses,Bird flu, RNA virus, DNA virus, adenovirus, poxvirus, Picornavirus,Togavirus, Orthomyxovirus, Retrovirus or Hepadnovirus), bacteria(including but not limited to Gram-negative, Gram-positive, Atypical,Staphylococcus, Streptococcus, E. Coli, Salmonella, Helicobacter pylori,meningitis, gonorrhea, Chlamydiaceae, Mycoplasmataceae, etc), fungus,protozoa, helminth, worms, prion, parasite, or other microbe.

In certain embodiments, the condition treated with a compound of thepresent invention is a disorder related to abnormal cellularproliferation. Abnormal cellular proliferation, notablyhyperproliferation, can occur as a result of a wide variety of factors,including genetic mutation, infection, exposure to toxins, autoimmunedisorders, and benign or malignant tumor induction.

There are a number of skin disorders associated with cellularhyperproliferation. Psoriasis, for example, is a benign disease of humanskin generally characterized by plaques covered by thickened scales. Thedisease is caused by increased proliferation of epidermal cells ofunknown cause. Chronic eczema is also associated with significanthyperproliferation of the epidermis. Other diseases caused byhyperproliferation of skin cells include atopic dermatitis, lichenplanus, warts, pemphigus vulgaris, actinic keratosis, basal cellcarcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include blood vesselproliferation disorders, fibrotic disorders, autoimmune disorders,graft-versus-host rejection, tumors and cancers.

Blood vessel proliferative disorders include angiogenic and vasculogenicdisorders. Proliferation of smooth muscle cells in the course ofdevelopment of plaques in vascular tissue cause, for example,restenosis, retinopathies and atherosclerosis. Both cell migration andcell proliferation play a role in the formation of atheroscleroticlesions.

Fibrotic disorders are often due to the abnormal formation of anextracellular matrix. Examples of fibrotic disorders include hepaticcirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosisis characterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. Hepatic cirrhosis cancause diseases such as cirrhosis of the liver. An increasedextracellular matrix resulting in a hepatic scar can also be caused byviral infection such as hepatitis. Lipocytes appear to play a major rolein hepatic cirrhosis.

Mesangial disorders are brought about by abnormal proliferation ofmesangial cells. Mesangial hyperproliferative cell disorders includevarious human renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic micro-angiopathysyndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis.Rheumatoid arthritis is generally considered an autoimmune disease thatis thought to be associated with activity of autoreactive T cells, andto be caused by autoantibodies produced against collagen and IgE.

Other disorders that can include an abnormal cellular proliferativecomponent include Bechet's syndrome, acute respiratory distress syndrome(ARDS), ischemic heart disease, post-dialysis syndrome, leukemia,acquired immune deficiency syndrome, vasculitis, lipid histiocytosis,septic shock and inflammation in general.

Cutaneous contact hypersensitivity and asthma are just two examples ofimmune responses that can be associated with significant morbidity.Others include atopic dermatitis, eczema, Sjogren's Syndrome, includingkeratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopeciaareata, allergic responses due to arthropod bite reactions, Crohn'sdisease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis,ulcerative colitis, cutaneous lupus erythematosus, scleroderma,vaginitis, proctitis, and drug eruptions. These conditions may result inany one or more of the following symptoms or signs: itching, swelling,redness, blisters, crusting, ulceration, pain, scaling, cracking, hairloss, scarring, or oozing of fluid involving the skin, eye, or mucosalmembranes.

In atopic dermatitis, and eczema in general, immunologically mediatedleukocyte infiltration (particularly infiltration of mononuclear cells,lymphocytes, neutrophils, and eosinophils) into the skin importantlycontributes to the pathogenesis of these diseases. Chronic eczema alsois associated with significant hyperproliferation of the epidermis.Immunologically mediated leukocyte infiltration also occurs at sitesother than the skin, such as in the airways in asthma and in the tearproducing gland of the eye in keratoconjunctivitis sicca.

In one non-limiting embodiment compounds of the present invention areused as topical agents in treating contact dermatitis, atopicdermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome,including keratoconjunctivitis sicca secondary to Sjogren's Syndrome,alopecia areata, allergic responses due to arthropod bite reactions,Crohn's disease, aphthous ulcer, iritis, conjunctivitis,keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma,cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, anddrug eruptions. The novel method may also be useful in reducing theinfiltration of skin by malignant leukocytes in diseases such as mycosisfungoides. These compounds can also be used to treat anaqueous-deficient dry eye state (such as immune mediatedkeratoconjunctivitis) in a patient suffering therefrom, by administeringthe compound topically to the eye.

Disease states which may be treated according to the present inventioninclude, for example, asthma, autoimmune diseases such as multiplesclerosis, various cancers, ciliopathies, cleft palate, diabetes, heartdisease, hypertension, inflammatory bowel disease, mental retardation,mood disorder, obesity, refractive error, infertility, Angelmansyndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease,Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis,Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria,Polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome,Sickle-cell disease, Tay-Sachs disease, Turner syndrome.

Further disease states or conditions which may be treated by thedisclosed compounds according to the present invention includeAlzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig'sdisease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attentiondeficit hyperactivity disorder, Autism, Bipolar disorder, Chronicfatigue syndrome, Chronic obstructive pulmonary disease, Crohn'sdisease, Coronary heart disease, Dementia, Depression, Diabetes mellitustype 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barre syndrome,Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis,Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panicdisorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis,Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourettesyndrome, Vasculitis.

Still additional disease states or conditions which can be treated bythe disclosed compounds according to the present invention includeaceruloplasminemia, Achondrogenesis type II, achondroplasia,Acrocephaly, Gaucher disease type 2, acute intermittent porphyria,Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency,adenylosuccinate lyase deficiency, Adrenogenital syndrome,Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency,Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema,amyotrophic lateral sclerosis Alstrom syndrome, Alexander disease,Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabrydisease, androgen insensitivity syndrome, Anemia Angiokeratoma CorporisDiffusum, Angiomatosis retinae (von Hippel-Lindau disease) Apertsyndrome, Arachnodactyly (Marfan syndrome), Stickler syndrome,Arthrochalasis multiplex congenital (Ehlers-Danlos syndrome#arthrochalasia type) ataxia telangiectasia, Rett syndrome, primarypulmonary hypertension, Sandhoff disease, neurofibromatosis type II,Beare-Stevenson cutis gyrata syndrome, Mediterranean fever, familial,Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dube syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Jackson-Weisssyndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weisssyndrome, Kidney diseases, including hyperoxaluria, Klinefelter'ssyndrome, Kniest dysplasia, Lacunar dementia, Langer-Saldinoachondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies).

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue(solid) or cells (non-solid) that grow by cellular proliferation, oftenmore rapidly than normal and continues to grow after the stimuli thatinitiated the new growth cease. Malignant neoplasms show partial orcomplete lack of structural organization and functional coordinationwith the normal tissue and most invade surrounding tissues, canmetastasize to several sites, are likely to recur after attemptedremoval and may cause the death of the patient unless adequatelytreated. As used herein, the term neoplasia is used to describe allcancerous disease states and embraces or encompasses the pathologicalprocess associated with malignant hematogenous, ascitic and solidtumors. Exemplary cancers which may be treated by the present disclosedcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

IV. Combination Therapy

The disclosed compounds of Formula I, II, III, IV, V and VI can be usedin an effective amount alone or in combination with another compound ofthe present invention or another bioactive agent to treat a host such asa human with a disorder as described herein.

The term “bioactive agent” is used to describe an agent, other than theselected compound according to the present invention, which can be usedin combination or alternation with a compound of the present inventionto achieve a desired result of therapy. In one embodiment, the compoundof the present invention and the bioactive agent are administered in amanner that they are active in vivo during overlapping time periods, forexample, have time-period overlapping Cmax, Tmax, AUC or otherpharmacokinetic parameter. In another embodiment, the compound of thepresent invention and the bioactive agent are administered to a host inneed thereof that do not have overlapping pharmacokinetic parameter,however, one has a therapeutic impact on the therapeutic efficacy of theother.

In one aspect of this embodiment, the bioactive agent is an immunemodulator, including but not limited to a checkpoint inhibitor,including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor,PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor,V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, smallmolecule, peptide, nucleotide, or other inhibitor. In certain aspects,the immune modulator is an antibody, such as a monoclonal antibody.

PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by bindingto the PD-1 receptor, and in turn inhibit immune suppression include,for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab,AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDIO680(AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1(Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042(Tesaro), and the PD-Li/VISTA inhibitor CA-170 (Curis Inc.). PD-L1inhibitors that block the interaction of PD-1 and PD-L1 by binding tothe PD-L1 receptor, and in turn inhibits immune suppression, include forexample, atezolizumab (Tecentriq), durvalumab (AstraZeneca andMedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb).CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immunesuppression include, but are not limited to, ipilimumab, tremelimumab(AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3checkpoint inhibitors, include, but are not limited to, BMS-986016(Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (PrimaBioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013(MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

In yet another embodiment, one of the active compounds described hereincan be administered in an effective amount for the treatment of abnormaltissue of the female reproductive system such as breast, ovarian,endometrial, or uterine cancer, in combination or alternation with aneffective amount of an estrogen inhibitor including but not limited to aSERM (selective estrogen receptor modulator), a SERD (selective estrogenreceptor degrader), a complete estrogen receptor degrader, or anotherform of partial or complete estrogen antagonist or agonist. Partialanti-estrogens like raloxifene and tamoxifen retain some estrogen-likeeffects, including an estrogen-like stimulation of uterine growth, andalso, in some cases, an estrogen-like action during breast cancerprogression which actually stimulates tumor growth. In contrast,fulvestrant, a complete anti-estrogen, is free of estrogen-like actionon the uterus and is effective in tamoxifen-resistant tumors.Non-limiting examples of anti-estrogen compounds are provided in WO2014/19176 assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, andU.S. Pat. Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US2015/0005286, WO 2014/205136, and WO 2014/205138. Additionalnon-limiting examples of anti-estrogen compounds include: SERMS such asanordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphenecitrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen,toremifene, and fulvestratnt; aromatase inhibitors such asaminoglutethimide, testolactone, anastrozole, exemestane, fadrozole,formestane, and letrozole; and antigonadotropins such as leuprorelin,cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate,delmadinone acetate, dydrogesterone, medroxyprogesterone acetate,megestrol acetate, nomegestrol acetate, norethisterone acetate,progesterone, and spironolactone. Other estrogenic ligands that can beused according to the present invention are described in U.S. Pat. Nos.4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011/156518, U.S. Pat.Nos. 8,455,534 and 8,299,112, 9,078,871; 8,853,423; 8,703,810; US2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO2014/191726, WO 2012/084711; WO 2002/013802; WO 2002/004418; WO2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO2002/003975; WO 2006/078834; U.S. Pat. No. 6,821,989; US 2002/0128276;U.S. Pat. No. 6,777,424; US 2002/0016340; U.S. Pat. Nos. 6,326,392;6,756,401; US 2002/0013327; U.S. Pat. Nos. 6,512,002; 6,632,834; US2001/0056099; U.S. Pat. Nos. 6,583,170; 6,479,535; WO 1999/024027; U.S.Pat. No. 6,005,102; EP 0802184; U.S. Pat. Nos. 5,998,402; 5,780,497,5,880,137, WO 2012/048058 and WO 2007/087684.

In another embodiment, an active compounds described herein can beadministered in an effective amount for the treatment of abnormal tissueof the male reproductive system such as prostate or testicular cancer,in combination or alternation with an effective amount of an androgen(such as testosterone) inhibitor including but not limited to aselective androgen receptor modulator, a selective androgen receptordegrader, a complete androgen receptor degrader, or another form ofpartial or complete androgen antagonist. In one embodiment, the prostateor testicular cancer is androgen-resistant. Non-limiting examples ofanti-androgen compounds are provided in WO 2011/156518 and U.S. Pat.Nos. 8,455,534 and 8,299,112. Additional non-limiting examples ofanti-androgen compounds include: enzalutamide, apalutamide, cyproteroneacetate, chlormadinone acetate, spironolactone, canrenone, drospirenone,ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

In one embodiment, the bioactive agent is an ALK inhibitor. Examples ofALK inhibitors include but are not limited to Crizotinib, Alectinib,ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026,PF-06463922, entrectinib (RXDX-101), and AP26113.

In one embodiment, the bioactive agent is an EGFR inhibitor. Examples ofEGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa),afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso),olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816),PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272);avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988(Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146,WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

In one embodiment, the bioactive agent is an HER-2 inhibitor. Examplesof HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumabemtansine, and pertuzumab.

In one embodiment, the bioactive agent is a CD20 inhibitor. Examples ofCD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab,tositumomab, and ocrelizumab.

In one embodiment, the bioactive agent is a JAK3 inhibitor. Examples ofJAK3 inhibitors include tasocitinib.

In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples ofBCL-2 inhibitors include venetoclax, ABT-199(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide),ABT-737(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263((R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),GX15-070 (obatoclax mesylate,(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid))), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester),pogosin, ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate,Nilotinib-d3, TW-37(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide),Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, orG3139 (Oblimersen).

In one embodiment, the bioactive agent is a kinase inhibitor. In oneembodiment, the kinase inhibitor is selected from a phosphoinositide3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor,or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

Examples of PI3 kinase inhibitors include but are not limited toWortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib,Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib,GS-9820, BKM120, GDC-0032 (Taselisib)(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; orMethyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide),GSK2126458(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide)(omipalisib), TGX-221((+)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one),GSK2636771(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid dihydrochloride), KIN-193((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoicacid), TGR-1202/RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one),AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz),AS 252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione),CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide),Buparlisib(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine),GDC-0941(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine),GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)),SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate),PF-05212384(N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N′-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile)(dactolisib), XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide),and GSK1059615(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),PX886([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216,pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173,VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75,PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib,IC-87114, TGI100713, CH₅₁₃₂₇₉₉, PKI-402, copanlisib (BAY 80-6946), XL147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424,AS-604850, apitolisib (GDC-0980; RG7422), and the structure described inWO2014/071109 having the formula:

Examples of BTK inhibitors include ibrutinib (also known asPCI-32765)(Imbruvica™)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics) (see US Patent Publication No 2011/0117073,incorporated herein in its entirety), Dasatinib([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide],LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl)propenamide), GDC-0834([R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide],CGI-5604-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide,CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide),CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide),CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one),GDC-0834((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),GDC-0837((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), QL-47(1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one),and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one),and other molecules capable of inhibiting BTK activity, for examplethose BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology& Oncology, 2013, 6:59, the entirety of which is incorporated herein byreference.

Syk inhibitors include, for example, Cerdulatinib(4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide),entospletinib(6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine),fostamatinib([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyldihydrogen phosphate), fostamatinib disodium salt (sodium(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methylphosphate), BAY 61-3606(2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamideHCl), RO9021(6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylicacid amide), imatinib (Gleevac;4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide),staurosporine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide),PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide),PRT-062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), R112(3,3′-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348(3-Ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one),piceatannol (3-Hydroxyresveratol), YM193306 (see Singh et al. Discoveryand Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (seeSingh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), Compound D (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), PRT060318 (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), luteolin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), apigenin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), quercetin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), fisetin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), myricetin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), morin (see Singh et al.Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J.Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein).

In one embodiment, the bioactive agent is a MEK inhibitor. MEKinhibitors are well known, and include, for example,trametinib/GSK1120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide),selumetinib(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC 1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),refametinib/BAY869766/RDEAl 19(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide),R05126766(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH₄₉₈₇₆₅₅(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2y1)methyl)benzamide),or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2 hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH,PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

In one embodiment, the bioactive agent is a Raf inhibitor. Rafinhibitors are known and include, for example, Vemurafinib(N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide),sorafenib tosylate(4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4-methylbenzenesulfonate),AZ628(3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide),NVP-BHG712(4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide),RAF-265(1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine),2-Bromoaldisine(2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf KinaseInhibitor IV(2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol),Sorafenib N-Oxide(4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N-Methyl-2pyridinecarboxaMide1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628,Sf590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818(Encorafenib).

In one embodiment, the bioactive agent is an AKT inhibitor, includingbut not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401),GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine,a FLT-3 inhibitor, including but not limited to, P406, Dovitinib,Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518),ENMD-2076, and KW-2449, or a combination thereof.

In one embodiment, the bioactive agent is an mTOR inhibitor. Examples ofmTOR inhibitors include but are not limited to rapamycin and itsanalogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus,and deforolimus. Examples of MEK inhibitors include but are not limitedto tametinib/GSK1120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide),selumetinob(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol)(cobimetinib), refametinib/BAY869766/RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6carboxamide), R05126766(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

In one embodiment, the bioactive agent is a RAS inhibitor. Examples ofRAS inhibitors include but are not limited to Reolysin and siG12D LODER.

In one embodiment, the bioactive agent is a HSP inhibitor. HSPinhibitors include but are not limited to Geldanamycin or17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.

Additional bioactive compounds include, for example, everolimus,trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693,RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258,GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054,PHA-739358, R-763, AT-9263, aFLT-3 inhibitor, a VEGFR inhibitor, anaurora kinase inhibitor, a PIK-1 modulator, an HDAC inhbitor, a c-METinhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, ananti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinasekinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab,amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin,ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan,tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111,131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan,IL13-PE38QQR, INO 1001, IPdR₁KRX-0402, lucanthone, LY317615, neuradiab,vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin,ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide,gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

In one embodiment, the bioactive agent is selected from, but are notlimited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®),Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®),trastuzumab-DM1, Pertuzumab (Perjeta™), Lapatinib (Tykerb®), Gefitinib(Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab(Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat(Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin(Panretin®), Tretinoin (Vesanoid®), Carfilizomib (Kyprolis™),Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept(Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib(Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

In certain aspects, the bioactive agent is an anti-inflammatory agent, achemotherapeutic agent, a radiotherapeutic, an additional therapeuticagent, or an immunosuppressive agent.

Suitable chemotherapeutic bioactive agents include, but are not limitedto, a radioactive molecule, a toxin, also referred to as cytotoxin orcytotoxic agent, which includes any agent that is detrimental to theviability of cells, and liposomes or other vesicles containingchemotherapeutic compounds. General anticancer pharmaceutical agentsinclude: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®),Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®),Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase(Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide(VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®),Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone(Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib(Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples ofadditional suitable chemotherapeutic agents include but are not limitedto 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine,6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylatingagent, allopurinol sodium, altretamine, amifostine, anastrozole,anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum(II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, anantibiotic, an antimetabolite, asparaginase, BCG live (intravesical),betamethasone sodium phosphate and betamethasone acetate, bicalutamide,bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin,capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU),Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens,Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasinB, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerlyactinomycin), daunirubicin HCL, daunorucbicin citrate, denileukindiftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione,Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coliL-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterifiedestrogens, estradiol, estramustine phosphate sodium, ethidium bromide,ethinyl estradiol, etidronate, etoposide citrororum factor, etoposidephosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate,fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids,goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea,idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole,leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine,lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesteroneacetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna,methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane,mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL,paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL,plimycin, polifeprosan 20 with carmustine implant, porfimer sodium,procaine, procarbazine HCL, propranolol, rituximab, sargramostim,streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone,tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL,toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastinesulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that can be administered in combinationwith a degronimer disclosed herein can include bevacizumab, sutinib,sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib,vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522),cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab,dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine,atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab,dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib,carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir,nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat,mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin,talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib,dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib,bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991,ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fulvestrant(Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398,necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

In one aspect of the invention, the disclosed compound is administeredin combination with an anti-infective agent, for example but not limitedto an anti-HIV agent, anti-HCV agent, anti-HBV agent, or otheranti-viral or anti-bacterial agent. In one embodiment, the anti-HIVagent can be, but is not limited to, for example, a nucleoside reversetranscriptase inhibitor (NRTI), other non-nucloeoside reversetranscriptase inhibitor, protease inhibitor, fusion inhibitor, amongothers. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)include, but are not limited to, Abacavir or ABC (Ziagen), Didanosine orddl (Videx), Emtricitabine or FTC (Emtriva), Lamivudine or 3TC (Epivir),ddC (zalcitabine), Stavudine or d4T (Zerit), Tenofovircor TDF (Viread),D-D4FC (Reverset), and Zidovudine or AZT or ZDV (Retrovir).Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) include, butare not limited to, Delavirdine (Rescriptor), Efavirenz (Sustiva),Etravirine (Intelence), Nevirapine (Viramune), and Rilpivirine(Edurant). Anti-HIV Protease Inhibitors (PIs) include, but are notlimited to, Atazanavir or ATV (Reyataz), Darunavir or DRV (Prezista),Fosamprenavir or FPV (Lexiva), Indinavir or IDV (Crixivan),Lopinavir+ritonavir, or LPV/r (Kaletra), Nelfinavir or NFV (Viracept),Ritonavir or RTV (Norvir), Saquinavir or SQV (Invirase), Tipranavir, orTPV (Aptivus), Cobicistat (Tybost), Atazanavir+cobicistat, or ATV/COBI(Evotaz), Darunavir+cobicistat, or DRV/COBI (Prezcobix). Anti-HIV FusionInhibitors include, but are not limited to, Enfuvirtide or ENF or T-20(Fuzeon). Anti-HIV also include, but are not limited to, Maraviroc orMVC (Selzentry). Anti-HIV Integrase Inhibitors include, but are notlimited to Dolutegravir (Tivicay), Elvitegravir (Vitekta), Raltegravir(Isentress). Anti-HIV combinations agents includeAbacavir+Dolutegravir+lamivudine,or ABC/DTG/3TC (Triumeq),Abacavir+lamivudine or ABC/3TC (Epzicom),Abacavir+lamivudine+zidovudine, or ABC/3TC/ZDV (Trizivir),Efavirenz+emtricitabine+tenofovir or EFV/FTC/TDF (Atripla, Tribuss),elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide orEVG/COBI/FTC/TAF or ECF/TAF (Genvoya; (Stribild),emtricitabine+rilpivirine+tenofovir or FTC/RPV/TAF (Odefsey);Emtricitabine+rilpivirine+tenofovir or FTC/RPV/TDF (Complera),Emtricitabine+tenofovir or TAF/FTC (Descovy), emtricitabine andtenofovir disoproxil fumarate (Truvada), and Lamivudine+zidovudine or3TC/ZDV (Combivir). Other anti-HIV compounds include, but are notlimited to Racivir, L-FddC, L-FD4C, SQVM (Saquinavir mesylate), IDV(Indinavir), SQV (Saquinavir), APV (Amprenavir), LPV (Lopinavir), fusioninhibitors such as T20, among others, fuseon and mixtures thereof,including anti-HIV compounds presently in clinical trials or indevelopment.

Other anti-HIV agents which may be used in co-administration with thedisclosed compounds according to the present invention. NNRTIs may beselected from the group consisting of nevirapine (BI-R6-587),delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781(N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide),etravirine (TMC125), Trovirdine (Ly300046.HCl), HI-236, HI-240, HI-280,HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin(TJN-151) ADAM-II (Methyl3′,3′-dichloro-4′,4″-dimethoxy-5′,5″-bis(methoxycarbonyl)-6,6-diphenylhexenoate),Methyl3-Bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate(Alkenyldiarylmethane analog, Adam analog),(5-chloro-3-(phenylsulfinyl)-2′-indolecarboxamide), AAP-BHAP (U-104489or PNU-104489), Capravirine (AG-1549, 5-1153), atevirdine (U-87201E),aurin tricarboxylic acid (SD-095345),1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[3-(Ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine,1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[[5-(Methylsulfonyloxy)-2-indoyly)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,U88204E, Bis(2-nitrophenyl)sulfone (NSC 633001), Calanolide A(NSC675451), Calanolide B,6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961,E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M(1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), InophyllumP, L-737,126, Michellamine A (NSC650898), Michellamine B (NSC649324),Michellamine F,6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil,6-(3,5-Dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU(NSC 648400), Oltipraz(4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione),N-{2-(2-Chloro-6-fluorophenethyl]-N′-(2-thiazolyl)thiourea (PETT Cl, Fderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-bromopyridyl)]thiourea {PETTderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-methylpyridyl]thiourea {PETTPyridyl derivative),N-[2-(3-Fluorofuranyl)ethyl]-N′-[2-(5-chloropyridyl)]thiourea,N-[2-(2-Fluoro-6-ethoxyphenethyl)]-N′-[2-(5-bromopyridyl)]thiourea,N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea (LY-73497), L-697,639,L-697,593, L-697,661,342-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pypridin-2(1H)-thione(2-Pyridinone Derivative),3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pypridin-2(1H)-thione,R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, 5-2720,Suramin Sodium, TBZ (Thiazolobenzimidazole, NSC 625487),Thiazoloisoindol-5-one,(+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, Tivirapine (R86183), UC-38 and UC-84, among others.

In one aspect of the invention, the disclosed compound when used totreat an HCV infection can be administered in combination with anotheranti-HCV agent. Anti-HCV agents are known in the art. To date, a numberof fixed dose drug combinations have been approved for the treatment ofHCV. Harvoni® (Gilead Sciences, Inc.) contains the NS5A inhibitorledipasvir and the NS5B inhibitor sofosbuvir. Technivie™ (AbbVie, Inc.)is a fixed-dose combination containing ombitasvir, an NS5A inhibitor;paritaprevir, an NS3/4A protease inhibitor; and ritonavir, a CYP3Ainhibitor. Daklinza™ (daclatasvir, Bristol-Myers Squibb) is a HCV NS5Ainhibitor indicated for use with sofosbuvir for the treatment of chronicgenotype 3 infection. Zepatier™ (Merck & Co.) has recently been approvedfor the treatment of chronic HCV genotypes 1 and 4. Zepatier™ is afixed-dose combination product containing elbasvir, an HCV NS5Ainhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. Zepatier™is indicated with or without ribavirin. Epclusa® (Gilead Sciences, Inc.)is a fixed-dose combination tablet containing sofosbuvir andvelpatasvir. Additional anti-HCV agents and combinations thereof includethose described in U.S. Pat. Nos. 9,382,218; 9,321,753; 9,249,176;9,233,974; 9,221,833; 9,211,315; 9,194,873; 9,186,369; 9,180,193;9,156,823; 9,138,442; 9,133,170; 9,108,999; 9,090,559; 9,079,887;9,073,943; 9,073,942; 9,056,090; 9,051,340; 9,034,863; 9,029,413;9,011,938; 8,987,302; 8,945,584; 8,940,718; 8,927,484; 8,921,341;8,884,030; 8,841,278; 8,822,430; 8,772,022; 8,765,722; 8,742,101;8,741,946; 8,674,085; 8,673,288; 8,669,234; 8,663,648; 8,618,275;8,580,252; 8,575,195; 8,575,135; 8,575,118; 8,569,302; 8,524,764;8,513,298; 8,501,714; 8,404,651; 8,273,341; 8,257,699; 8,197,861;8,158,677; 8,105,586; 8,093,353; 8,088,368; 7,897,565; 7,871,607;7,846,431; 7,829,081; 7,829,077; 7,824,851; 7,572,621; and 7,326,536;Patents assigned to Alios: U.S. Pat. Nos. 9,365,605; 9,346,848;9,328,119; 9,278,990; 9,249,174; 9,243,022; 9,073,960; 9,012,427;8,980,865; 8,895,723; 8,877,731; 8,871,737; 8,846,896 and 8,772,474;Achillion U.S. Pat. Nos. 9,273,082; 9,233,136; 9,227,952; 9,133,115;9,125,904; 9,115,175; 9,085,607; 9,006,423; 8,946,422; 8,835,456;8,809,313; 8,785,378; 8,614,180; 8,445,430; 8,435,984; 8,183,263;8,173,636; 8,163,693; 8,138,346; 8,114,888; 8,106,209; 8,088,806;8,044,204; 7,985,541; 7,906,619; 7,902,365; 7,767,706; 7,741,334;7,718,671; 7,659,399; 7,476,686; 7,439,374; 7,365,068; 7,199,128; and7,094,807; Cocrystal Pharma Inc. 9,181,227; 9,173,893; 9,040,479 and8,771,665; Gilead Sciences U.S. Pat. Nos. 9,353,423; 9,346,841;9,321,800; 9,296,782; 9,296,777; 9,284,342; 9,238,039; 9,216,996;9,206,217; 9,161,934; 9,145,441; 9,139,604; 9,090,653; 9,090,642;9,085,573; 9,062,092; 9,056,860; 9,045,520; 9,045,462; 9,029,534;8,980,878; 8,969,588; 8,962,652; 8,957,046; 8,957,045; 8,946,238;8,933,015; 8,927,741; 8,906,880; 8,889,159; 8,871,785; 8,841,275;8,815,858; 8,809,330; 8,809,267; 8,809,266; 8,779,141; 8,765,710;8,759,544; 8,759,510; 8,735,569; 8,735,372; 8,729,089; 8,722,677;8,716,264; 8,716,263; 8,716,262; 8,697,861; 8,664,386; 8,642,756;8,637,531; 8,633,309; 8,629,263; 8,618,076; 8,592,397; 8,580,765;8,569,478; 8,563,530; 8,551,973; 8,536,187; 8,513,186; 8,513,184;8,492,539; 8,486,938; 8,481,713; 8,476,225; 8,420,597; 8,415,322;8,338,435; 8,334,270; 8,329,926; 8,329,727; 8,324,179; 8,283,442;8,263,612; 8,232,278; 8,178,491; 8,173,621; 8,163,718; 8,143,394;patents assigned to Idenix, acquired by Merck, include U.S. Pat. Nos.9,353,100; 9,309,275; 9,296,778; 9,284,307; 9,249,173; 9,243,025;9,211,300; 9,187,515; 9,187,496, 9,109,001; 8,993,595; 8,951,985;8,691,788; 8,680,071; 8,637,475; 8,507,460; 8,377,962; 8,362,068;8,343,937; 8,299,038; 8,193, 372; 8,093,379; 7,951,789; 7,932,240;7,902,202; 7,662,798; 7,635,689; 7,625,875; 7,608,600; 7,608,597;7,582,618; 7,547,704; 7,456,155; 7,384,924; 7,365,057; 7,192,936;7,169,766; 7,163,929; 7,157,441; 7,148,206; 7,138,376; 7,105,493;6,914,054 and 6,812,219; patents assigned to Merck include U.S. Pat.Nos. 9,364,482; 9,339,541; 9,328,138; 9,265,773; 9,254,292; 9,243,002;9,242,998; 9,242,988; 9,242,917; 9,238,604; 9,156,872; 9,150,603;9,139,569; 9,120,818; 9,090,661; 9,073,825; 9,061,041; 8,987,195;8,980,920; 8,927,569; 8,871,759; 8,828,930; 8,772,505; 8,715,638;8,697,694; 8,637,449; 8,609,635; 8,557,848; 8,546,420; 8,541,434;8,481,712; 8,470,834; 8,461,107; 8,404,845; 8,377,874; 8,377,873;8,354,518; 8,309,540; 8,278,322; 8,216,999; 8,148,349; 8,138,164;8,080,654; 8,071,568; 7,973,040; 7,935,812; 7,915,400; 7,879,815;7,879,797; 7,632,821; 7,569,374; 7,534,767; 7,470,664 and 7,329,732;patent application publication US 2013/0029904 to Boehringer IngelheimGMBH and US 2014/0113958 to Stella Aps.

In one embodiment, the additional therapy is a monoclonal antibody(MAb). Some MAbs stimulate an immune response that destroys cancercells. Similar to the antibodies produced naturally by B cells, theseMAbs may “coat” the cancer cell surface, triggering its destruction bythe immune system. For example, bevacizumab targets vascular endothelialgrowth factor (VEGF), a protein secreted by tumor cells and other cellsin the tumor's microenvironment that promotes the development of tumorblood vessels. When bound to bevacizumab, VEGF cannot interact with itscellular receptor, preventing the signaling that leads to the growth ofnew blood vessels. Similarly, cetuximab and panitumumab target theepidermal growth factor receptor (EGFR), and trastuzumab targets thehuman epidermal growth factor receptor 2 (HER-2). MAbs that bind to cellsurface growth factor receptors prevent the targeted receptors fromsending their normal growth-promoting signals. They may also triggerapoptosis and activate the immune system to destroy tumor cells.

In one aspect of the present invention, the bioactive agent is animmunosuppressive agent. The immunosuppressive agent can be acalcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTORinhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus(RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus,biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine,campath 1H, a S1P receptor modulator, e.g. fingolimod or an analoguethereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof,e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil(CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD25, anti-IL2R, Basiliximab (SVIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,aspirin and ibuprofen.

V. Pharmaceutical Compositions

The compounds of Formula I, II, III, VI, V and VI as disclosed hereincan be administered as the neat chemical, but are more typicallyadministered as a pharmaceutical composition, that includes an effectiveamount for a host, typically a human, in need of such treatment for anyof the disorders described herein. Accordingly, the disclosure providespharmaceutical compositions comprising an effective amount of thedisclosed compound or pharmaceutically acceptable salt thereof togetherwith at least one pharmaceutically acceptable carrier for any of theuses described herein. The pharmaceutical composition may contain thedisclosed compound or salt as the only active agent, or, in analternative embodiment, the disclosed compound and at least oneadditional active agent.

Compounds disclosed herein may be administered by any suitable routedesired by the healthcare provider, including orally, topically,systemically, parenterally, by inhalation or spray, sublingually, viaimplant, including ocular implant, transdermally, via buccaladministration, rectally, as an ophthalmic solution, injection,including ocular injection, intraveneous, intra-arterial, intra-aortal,intracranial, subdermal, intraperitioneal, subcutaneous, transnasal,sublingual, or rectal or by other means, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers.

In general, the compositions of the disclosure will be administered in atherapeutically effective amount by the desired mode of administration.Suitable dosage ranges depend upon numerous factors such as the severityof the disease to be treated, the age and relative health of thesubject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compositions of the disclosurefor a given disease.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10,25, 50 or 100 mg to about 1000 mg, from about 100 mg to about 800 mg, orfrom about 50 to 500, 75 to 500, or 200 mg to about 600 mg of the activecompounds and optionally for example from about 0.1 mg to about 2000 mg,from about 10, 25, 50 or 100 mg to about 1000 mg, from about 50 to 500,75 to 500,from about 100 mg to about 800 mg, or from about 200 mg toabout 600 mg of an additional active agent in a unit dosage form.Examples are dosage forms with at least 0.1, 1, 5, 10, 25, 50, 100, 200,250, 300, 400, 500, 600, 700, 750 or 800 mg of active compound, or itssalt.

The therapeutically effective dosage of any active compound describedherein will be determined by the health care practitioner depending onthe condition, size and age of the patient as well as the route ofdelivery. In one non-limited embodiment, a dosage from about 0.1 toabout 200 mg/kg, from about 0.01 mg/kg to about 250 mg/kg body weight,more preferably about 0.1 mg/kg to up to about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 20 or 30 mg/kg, in at least one dose. In some embodiments, thedosage may be the amount of compound needed to provide a serumconcentration of the active compound of up to about 10 nM, 50 nM, 100nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1μM, 5 μM, 10 μM, 20 μM, 30 μM, or 40 μM.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a pill, an injectionor infusion solution, a capsule, a tablet, a syrup, a transdermal patch,a subcutaneous patch, a dry powder, an inhalation formulation, in amedical device, suppository, buccal, or sublingual formulation,parenteral formulation, or an ophthalmic solution. Some dosage forms,such as tablets and capsules, are subdivided into suitably sized unitdoses containing appropriate quantities of the active components, e.g.,an effective amount to achieve the desired purpose.

“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: MackPublishing Company, 1990). For example, sterile saline andphosphate-buffered saline at physiological pH can be used.Preservatives, stabilizers, dyes and even flavoring agents can beprovided in the pharmaceutical composition. For example, sodiumbenzoate, sorbic acid and esters of p-hydroxybenzoic acid can be addedas preservatives. Id. at 1449. In addition, antioxidants and suspendingagents can be used. Id. Carriers include excipients must be ofsufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the patient being treated. The carriercan be inert or it can possess pharmaceutical benefits of its own. Theamount of carrier employed in conjunction with the disclosed compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound, as described in moredetail herein.

Classes of carriers include, but are not limited to binders, bufferingagents, coloring agents, diluents, disintegrants, emulsifiers,flavorants, glidents, lubricants, preservatives, stabilizers,surfactants, tableting agents, and wetting agents. Some carriers may belisted in more than one class, for example vegetable oil may be used asa lubricant in some formulations and a diluent in others. Exemplarypharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Optional active agents may be included in a pharmaceuticalcomposition, which do not substantially interfere with the activity ofthe disclosed compounds of the present invention.

Additionally, auxiliary substances, such as wetting or emulsifyingagents, biological buffering substances, surfactants, and the like, canbe present in such vehicles. A biological buffer can be any solutionwhich is pharmacologically acceptable and which provides the formulationwith the desired pH, i.e., a pH in the physiologically acceptable range.Examples of buffer solutions include saline, phosphate buffered saline,Tris buffered saline, Hank's buffered saline, and the like.

Depending on the intended mode of administration, the pharmaceuticalcompositions can be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, can include other pharmaceutical agents, adjuvants,diluents, buffers, and the like.

Thus, the compositions of the disclosure can be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal orparenteral (including intramuscular, intra-arterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is intravenous or oral using a convenient daily dosageregimen which can be adjusted according to the degree of affliction.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,and the like, an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered can also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate, andthe like. Actual methods of preparing such dosage forms are known, orwill be apparent, to those skilled in this art; for example, seeRemington's Pharmaceutical Sciences, referenced above.

In yet another embodiment is the use of permeation enhancer excipientsincluding polymers such as: polycations (chitosan and its quaternaryammonium derivatives, poly-L-arginine, aminated gelatin); polyanions(N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers(carboxymethyl cellulose-cysteine, polycarbophil-cysteine,chitosan-thiobutylamidine, chitosan-thioglycolic acid,chitosan-glutathione conjugates).

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule or can be an aqueous or nonaqueoussolution, suspension or syrup. Tablets and capsules are preferred oraladministration forms. Tablets and capsules for oral use can include oneor more commonly used carriers such as lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. Typically, the compositions of the disclosure can be combinedwith an oral, non-toxic, pharmaceutically acceptable, inert carrier suchas lactose, starch, sucrose, glucose, methyl cellulose, magnesiumstearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol andthe like. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Suitable binders include starch, gelatin,natural sugars such as glucose or beta-lactose, corn sweeteners, naturaland synthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

When liquid suspensions are used, the active agent can be combined withany oral, non-toxic, pharmaceutically acceptable inert carrier such asethanol, glycerol, water, and the like and with emulsifying andsuspending agents. If desired, flavoring, coloring and/or sweeteningagents can be added as well. Other optional components for incorporationinto an oral formulation herein include, but are not limited to,preservatives, suspending agents, thickening agents, and the like.

Parenteral formulations can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solubilizationor suspension in liquid prior to injection, or as emulsions. Preferably,sterile injectable suspensions are formulated according to techniquesknown in the art using suitable carriers, dispersing or wetting agentsand suspending agents. The sterile injectable formulation can also be asterile injectable solution or a suspension in a nontoxic parenterallyacceptable diluent or solvent. Among the acceptable vehicles andsolvents that can be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils, fatty estersor polyols are conventionally employed as solvents or suspending media.In addition, parenteral administration can involve the use of a slowrelease or sustained release system such that a constant level of dosageis maintained.

Parenteral administration includes intraarticular, intravenous,intramuscular, intradermal, intraperitoneal, and subcutaneous routes,and include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and non-aqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. Administration via certain parenteralroutes can involve introducing the formulations of the disclosure intothe body of a patient through a needle or a catheter, propelled by asterile syringe or some other mechanical device such as an continuousinfusion system. A formulation provided by the disclosure can beadministered using a syringe, injector, pump, or any other devicerecognized in the art for parenteral administration.

Preferably, sterile injectable suspensions are formulated according totechniques known in the art using suitable carriers, dispersing orwetting agents and suspending agents. The sterile injectable formulationcan also be a sterile injectable solution or a suspension in a nontoxicparenterally acceptable diluent or solvent. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oils,fatty esters or polyols are conventionally employed as solvents orsuspending media. In addition, parenteral administration can involve theuse of a slow release or sustained release system such that a constantlevel of dosage is maintained.

Preparations according to the disclosure for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms can also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They can be sterilized by, forexample, filtration through a bacteria retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured using sterile water, or some other sterile injectablemedium, immediately before use.

Sterile injectable solutions are prepared by incorporating one or moreof the compounds of the disclosure in the required amount in theappropriate solvent with various of the other ingredients enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the various sterilized activeingredients into a sterile vehicle which contains the basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof. Thus, for example, a parenteralcomposition suitable for administration by injection is prepared bystirring 1.5% by weight of active ingredient in 10% by volume propyleneglycol and water. The solution is made isotonic with sodium chloride andsterilized.

Formulations suitable for rectal administration are typically presentedas unit dose suppositories. These may be prepared by admixing the activedisclosed compound with one or more conventional solid carriers, forexample, cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers which may be used include petroleum jelly, lanoline,polyethylene glycols, alcohols, transdermal enhancers, and combinationsof two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3 (6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. In one embodiment, microneedle patchesor devices are provided for delivery of drugs across or into biologicaltissue, particularly the skin. The microneedle patches or devices permitdrug delivery at clinically relevant rates across or into skin or othertissue barriers, with minimal or no damage, pain, or irritation to thetissue.

Formulations suitable for administration to the lungs can be deliveredby a wide range of passive breath driven and active power drivensingle/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

Additional non-limiting examples of drug delivery devices and methodsinclude, for example, US20090203709 titled “Pharmaceutical Dosage FormFor Oral Administration Of Tyrosine Kinase Inhibitor” (AbbottLaboratories); US20050009910 titled “Delivery of an active drug to theposterior part of the eye via subconjunctival or periocular delivery ofa prodrug”, US 20130071349 titled “Biodegradable polymers for loweringintraocular pressure”, U.S. Pat. No. 8,481,069 titled “Tyrosine kinasemicrospheres”, U.S. Pat. No. 8,465,778 titled “Method of making tyrosinekinase microspheres”, U.S. Pat. No. 8,409,607 titled “Sustained releaseintraocular implants containing tyrosine kinase inhibitors and relatedmethods”, U.S. Pat. No. 8,512,738 and US 2014/0031408 titled“Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986titled “Microsphere Drug Delivery System for Sustained IntraocularRelease”, U.S. Pat. No. 8,911,768 titled “Methods For TreatingRetinopathy With Extended Therapeutic Effect” (Allergan, Inc.); U.S.Pat. No. 6,495,164 titled “Preparation of injectable suspensions havingimproved injectability” (Alkermes Controlled Therapeutics, Inc.); WO2014/047439 titled “Biodegradable Microcapsules Containing FillingMaterial” (Akina, Inc.); WO 2010/132664 titled “Compositions And MethodsFor Drug Delivery” (Baxter International Inc. Baxter Healthcare SA);US20120052041 titled “Polymeric nanoparticles with enhanced drug loadingand methods of use thereof” (The Brigham and Women's Hospital, Inc.);US20140178475, US20140248358, and US20140249158 titled “TherapeuticNanoparticles Comprising a Therapeutic Agent and Methods of Making andUsing Same” (BIND Therapeutics, Inc.); U.S. Pat. No. 5,869,103 titled“Polymer microparticles for drug delivery” (Danbiosyst UK Ltd.); U.S.Pat. No. 8,628,801 titled “Pegylated Nanoparticles” (Universidad deNavarra); US2014/0107025 titled “Ocular drug delivery system” (JadeTherapeutics, LLC); U.S. Pat. No. 6,287,588 titled “Agent deliveringsystem comprised of microparticle and biodegradable gel with an improvedreleasing profile and methods of use thereof”, U.S. Pat. No. 6,589,549titled “Bioactive agent delivering system comprised of microparticleswithin a biodegradable to improve release profiles” (Macromed, Inc.);U.S. Pat. Nos. 6,007,845 and 5,578,325 titled “Nanoparticles andmicroparticles of non-linear hydrophilic hydrophobic multiblockcopolymers” (Massachusetts Institute of Technology); US20040234611,US20080305172, US20120269894, and US20130122064 titled “Ophthalmic depotformulations for periocular or subconjunctival administration (NovartisAg); U.S. Pat. No. 6,413,539 titled “Block polymer” (Poly-Med, Inc.); US20070071756 titled “Delivery of an agent to ameliorate inflammation”(Peyman); US 20080166411 titled “Injectable Depot Formulations AndMethods For Providing Sustained Release Of Poorly Soluble DrugsComprising Nanoparticles” (Pfizer, Inc.); U.S. Pat. No. 6,706,289 titled“Methods and compositions for enhanced delivery of bioactive molecules”(PR Pharmaceuticals, Inc.); and U.S. Pat. No. 8,663,674 titled“Microparticle containing matrices for drug delivery” (Surmodics).

VI. General Synthesis

Compounds of the present invention without stereocenters forconvenience. One skilled in the art will recognize that pure enantiomersand diastereomers can be prepared by methods known in the art. Examplesof methods to obtain optically active materials include at least thefollowing.

i) physical separation of crystals—a technique whereby macroscopiccrystals of the individual enantiomers are manually separated. Thistechnique can be used if crystals of the separate enantiomers exist,i.e., the material is a conglomerate, and the crystals are visuallydistinct;

ii) simultaneous crystallization—a technique whereby the individualenantiomers are separately crystallized from a solution of the racemate,possible only if the latter is a conglomerate in the solid state;

iii) enzymatic resolutions—a technique whereby partial or completeseparation of a racemate by virtue of differing rates of reaction forthe enantiomers with an enzyme;

iv) enzymatic asymmetric synthesis a synthetic technique whereby atleast one step of the synthesis uses an enzymatic reaction to obtain anenantiomerically pure or enriched synthetic precursor of the desiredenantiomer;

v) chemical asymmetric synthesis—a synthetic technique whereby thedesired enantiomer is synthesized from an achiral precursor tinderconditions that produce asymmetry (i.e., chirality) in the product,which may be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereomer separations—a technique whereby a racemic compound isreacted with an enantiomerically pure reagent (the chiral auxiliary)that converts the individual enantiomers to diastereomers. The resultingdiastereomers are then separated by chromatography or crystallization byvirtue of their now more distinct structural differences and the chiralauxiliary later removed to obtain the desired enantiomer;

vii) first- and second-order asymmetric transformations—a techniquewhereby diastereomers from the racemate equilibrate to yield apreponderance in solution of the diastereomer from the desiredenantiomer or where preferential crystallization of the diastereomerfrom the desired enantiomer perturbs the equilibrium such thateventually in principle all the material is converted to the crystallinediastereomer from the desired enantiomer. The desired enantiomer is thenreleased from the diastereomer;

viii) kinetic resolutions—this technique refers to the achievement ofpartial or complete resolution of a racemate (or of a further resolutionof a partially resolved compound) by virtue of unequal reaction rates ofthe enantiomers with a chiral, non-racemic reagent or catalyst tinderkinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors a synthetictechnique whereby the desired enantiomer is obtained from non-chiralstarting materials and where the stereochemical integrity is not or isonly minimally compromised over the course of the synthesis;

x) chiral liquid chromatography—a technique whereby the enantiomers of aracemate are separated in a liquid mobile phase by virtue of theirdiffering interactions with a stationary phase (including via chiralHPLC). The stationary phase can be made of chiral material or the mobilephase can contain an additional chiral material to provoke the differinginteractions;

xi) chiral gas chromatography—a technique whereby the racemate isvolatilized and enantiomers are separated by virtue of their differinginteractions in the gaseous mobile phase with a column containing afixed non-racemic chiral adsorbent phase;

xii) extraction with chiral solvents—a technique whereby the enantiomersare separated by virtue of preferential dissolution of one enantiomerinto a particular chiral solvent;

xiii) transport across chiral membranes—a technique whereby a racemateis placed in contact with a thin membrane barrier. The barrier typicallyseparates two miscible fluids, one containing the racemate, and adriving force such as concentration or pressure differential causespreferential transport across the membrane barrier. Separation occurs asa result of the non-racemic chiral nature of the membrane that allowsonly one enantiomer of the racemate to pass through.

xiv) simulated moving bed chromatography, is used in one embodiment. Awide variety of chiral stationary phases are commercially available.

The compounds described herein can be prepared by methods known by thoseskilled in the art. In one non-limiting example the disclosed compoundscan be made by the following schemes.

As shown in Scheme 1 compounds for use in the present invention can beprepared by chemically combining a Degron and a Linker followed bysubsequent addition of a Targeting Ligand. Similarly, in Scheme 2compounds for use in the present invention are prepared by chemicallycombing a Targeting Ligand and Linker first, followed by subsequentaddition of a Degron. As illustrated in the above and following schemes,compounds for use in the present invention can readily be synthesized byone skilled in the art in a variety of methods and chemical reactions.

Scheme 3: In Step 1, a nucleophilic Degron displaces a leaving group onthe Linker to make a Degron Linker fragment. In Step 2, the protectinggroup is removed by methods known in the art to free a nucleophilic siteon the linker. In Step 3, the nucleophilic Degron Linker fragmentdisplaces a leaving group on the Targeting Ligand to form a compound foruse in the present invention. In an alternative embodiment Step 1 and/orStep 2 is accomplished by a coupling reaction instead of a nucleophilicattack.

Scheme 4: In Step 1, a nucleophilic Targeting Ligand displaces a leavinggroup on the Linker to make a Targeting Ligand Linker fragment. In Step2, the protecting group is removed by methods known in the art to free anucleophilic site on the linker. In Step 3, the nucleophilic TargetingLigand Linker fragment displaces a leaving group on the Degron to form acompound for use in the present invention. In an alternative embodimentStep 1 and/or Step 2 is accomplished by a coupling reaction instead of anucleophilic attack.

Scheme 5, Scheme 6, and Scheme 7: In Step 1, a nucleophilic Linkerdisplaces a leaving group on the Degron to make a Degron Linkerfragment. In Step 2, the protecting group is removed by methods known inthe art to free a nucleophilic site on the linker. In Step 3, thenucleophilic Degron Linker fragment displaces a leaving group on theTargeting Ligand to form a compound of Formula I, Formula II, or FormulaIII. In an alternative embodiment Step 1 and/or Step 2 is accomplishedby a coupling reaction instead of a nucleophilic attack.

VII. Synthesis of Representative Compounds

In the following Schemes, R is the point of attachment to the linker.

3-Hydroxyphthalic anhydride

A solution of 3-nitrophthalic anhydride (1 equiv.) in acetone issubjected to catalytic reduction under hydrogen (60 psi) in the presenceof Raney nickel and anhydrous magnesium sulfate. After 2-3 hours, thesolution is warmed to 50° C., treated with Norite, filtered, andconcentrated in vacuo at room temperature. The residue is treated withethyl acetate, chilled and collected to give 3-aminophthalic anhydride.15 N sulfuric acid is cooled to 0° C., 3-aminophthalic anhydride (1equiv.) is added gradually with good stirring. After one hour, asolution of sodium nitrite (1 equiv.) in water is added slowly whilemaintaining the temperature below 5° C. After another 30 minutes, themixture is warmed to 80° C. and maintained at this temperature untilnitrogen evolution ceases. The now dark orange solution is diluted withwater and extracted with ether. The organic layer is dried with sodiumsulfate, filtered and shaken for two hours with finely powdered bariumchloride to remove traces of sulfuric acid. The solution is filtered andconcentrated and the resulting crude 3-hydroxyphthalic acid sublimes atabout 160-180° C. (0.2 mm.) to give 3-hydroxyphthalic anhydride. (J. Am.Chem. Soc., 1955, 77 (19), pp 5092-5095)

4-Hydroxythalidomide

A mixture of 3-hydroxyphthalic anhydride (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide 4-hydroxythalidomide.

4-Alkoxythalidomide

Alkyl halide (1 equiv.) is dissolved in MeCN. 4-hydroxythalidomide (1.1equiv.) and cesium carbonate (2.75 equiv.) are added and the mixture isheated at 80° C. overnight. The mixture is cooled to room temperatureand diluted water and extracted with chloroform and EtOAc. The combinedorganic layers are dried over sodium sulfate, filtered and concentrated.The crude is purified by column chromatography on silica gel to give4-alkoxythalidomide. (Science 2015, 348 (6241), 1376-1381).

General Procedure to Prepare Pomalidomide Derivatives:

4-Fluorothalidomide

A mixture of 3-fluorophthalic anhydride (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide 4-fluorothalidomide.

Pomalidomide Analogs

A mixture of amine (1 equiv.), 4-fluorothalidomide (1 equiv.) and DIEA(2 eq.) in dry DMF is stirred at 90° C. for 12 h. The mixture is cooledto room temperature, poured into water and extracted with ethyl acetate.The combined organic phases are washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Thecrude residue is purified by column chromatography on silica gel to givepomalidomide analogs. (Chem Biol. 2015 Jun. 18; 22(6):755-63.)

General Procedure to Prepare Lenalidomide Derivatives:

3-(7-Nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of a-aminoglutarimide (1.0 equiv.) and methyl2-(bromomethyl)-3-nitrobenzoate (1.3 equiv) in DMF is addedtriethylamine (3.0 equiv), and the mixture is heated to 75° C. andstirred for 20 h. Then it is cooled to RT and poured into LiCl (5% inH₂O). It is extracted with EtOAc, and the combined organic phases arewashed with LiCl (5% in H₂O) and saturated aqueous NaCl, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude is purified by columnchromatography on silica gel to give3-(7-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (Org. Lett., 2013,15(17), pp 4312-4315)

Lenalidomide

A mixture of 3-(7-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1equiv.) and palladium on activated carbon (10% wt) in THE ishydrogenated until the disappearance of the starting material. Themixture is filtered through Celite® and concentrated to givelenalidomide.

Lenalidomide Analogs

Alkyl halide (1 equiv.) is dissolved in DMF. Lenalidomide (1.1 equiv.)and potassium carbonate (2 equiv.) are added and the mixture is stirredat rt overnight. The mixture is diluted water and extracted with EtOAc.The combined organic layer is dried over sodium sulfate, filtered andconcentrated. The crude is purified by column chromatography on silicagel to give lenalidomide analogs.

General Procedure to Prepare Boc-Protected Glutarimide:

To a stirred solution of 4-fluorothalidomide (1.0 equiv.) in DMF isadded potassium carbonate (2.0 equiv.). The resulting solution is cooledto 0-5° C. and Boc anhydride (3.0 equiv.) is added slowly as a solutionin 1,4-dioxane (also cooled). The resulting mixture is stirred at 0° C.for 1 h and allowed to warm to room temperature overnight. Water is thenadded and the aqueous layer is extracted 2 times with DCM andconcentrated. The residue is purified by column chromatography on silicagel to obtain N-Boc 4-fluorothalidomide. (WO 2014/147531 A2)

Thal/Pom/Len Analogs with Variation on the Phthalimide Moiety

General Procedure to Prepare O-Aryl Thalidomide:

General Procedure Example 1: O-Pyrazole thalidomide

1-(3-Hydroxy-1H-pyrazol-1-yl)ethanone

A solution of 3-hydroxy-1H-pyrazole (1 equiv.) in pyridine is heated to95° C. A mixture consisting of acetic anhydride (1.05 equiv.) andpyridine is added over 20 min. After stirring at 95° C. for 2 h, allvolatiles are removed in vacuo and Et₂O is added to the residue. Theslurry is stirred overnight at rt. The solid was filtered off and washedwith Et₂O to give the 1-(3-hydroxy-1H-pyrazol-1-yl)ethanone.(ChemMedChem 2015, 10, 1184-1199)

tert-Butyl3-(4-((1-acetyl-1H-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate

1-(3-Hydroxy-1H-pyrazol-1-yl)ethanone (1 equiv.) is dissolved in DMF.NaH (1.5 equiv.) is added slowly and stirred at rt for 30 min.4-Fluorothalidomide (1 equiv.) is added and the solution is stirred atrt or 90° C. until the consumption of the starting materials. Thereaction is quenched with methanol and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography on silica gel to givetert-butyl3-(4-((1-acetyl-1H-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate.(PCT Int. Appl., 2015087234, 18 Jun. 2015)

tert-Butyl3-(4-((1H-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate

tert-Butyl3-(4-((1-acetyl-1H-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) is dissolved in a mixture of MeOH/THF (2:3). 10% NaOH isadded, and the solution is stirred at rt for 5 h. Then all the volatilesare removed in vacuo. The residue is diluted with EtOAc and water. Theaqueous phase was extracted with EtOAc. The combined organic layers arewashed with water and brine and dried (Na₂SO₄). Evaporation of all thevolatiles gives tert-butyl3-(4-((1H-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate.(PCT Int. Appl., 2015087234, 18 Jun. 2015)

tert-Butyl3-(4-((1-alkyl-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate

tert-Butyl3-(4-((1H-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) is dissolved in DMF and K₂CO₃ (2 equiv.) is added, followedby alkyl halide (1.2 equiv.). The mixture is stirred at rt overnight.The reaction is poured into water and extracted with EtOAc. The organiclayer is washed with water and brine, dried (Na₂SO₄), and concentrated.The residue is purified by column chromatography on silica gel to givetert-butyl3-(4-((1-alkyl-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate.

4-((1-Alkyl-pyrazol-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A solution of tert-butyl3-(4-((1-alkyl-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) in TFA/DCM (1:1) is stirred at rt overnight. Solvent isevaporated and the residue is purified by column chromatography onsilica gel to give4-((1-alkyl-pyrazol-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

General Procedure to Prepare N-Aryl Pomalidomide:

General Procedure Example 2: N-Pyrazole pomalidomide

tert-Butyl3-(4-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate

4-Chlorothalidomide (1 equiv.) and 3-amino-1-Boc-pyrazole (2 equiv.) aredissolved in dioxane. XantPhos (0.1 equiv.) and Cs₂CO₃ (2.5 equiv.) areadded and the mixture is degassed with nitrogen. Pd₂(dba)₃ (0.05 equiv.)is added and the mixture is sealed and heated at 80° C. overnight. Thereaction is poured into water and extracted with EtOAc. The organiclayer is washed with water and brine, dried (Na₂SO₄), and concentrated.The residue is purified by column chromatography on silica gel to givetert-butyl3-(4-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate.

4-((1H-Pyrazol-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A solution of tert-butyl3-(4-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) in TFA/DCM (1:1) is stirred at rt overnight. Solvent isevaporated and the residue is purified by column chromatography onsilica gel to give4-((1H-pyrazol-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

4-((1-Alkyl-pyrazol-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

4-((1H-pyrazol-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(1 equiv.) is dissolved in DMF and K₂CO₃ (1.2 equiv.) is added, followedby alkyl halide (1 equiv.). The mixture is stirred at rt overnight. Thereaction is poured into water and extracted with EtOAc. The organiclayer is washed with water and brine, dried (Na₂SO₄), and concentrated.The residue is purified by column chromatography on silica gel to give4-((1-alkyl-pyrazol-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

General Procedure to Prepare N-Aryl Lenalidomide:

General Procedure Example 3: N-Pyridyl lenalidomide

N-Pyridyl-Boc-Lenalidomide

Under argon, substituted 2-chloropyridine (1 equiv.) and lenalidomide(1.1 equiv.) are loaded into oven-dried vials, followed by the additionof palladium catalyst (1 mol %), NaOtBu (1.1 equiv.) and dry dioxane.The reaction is run at 70° C. After consumption of reactants or nofurther conversion, the reaction is quenched with aqueous NH₄Cl solutionand extracted with CH₂C₂. The organic layer is dried over Na₂SO₄ andconcentrated. The residue is purified by column chromatography on silicagel to give N-pyridyl-Boc-lenalidomide. (Org. Lett. 2003, 5, 1479-1482).

N-Pyridyl-lenalidomide

A solution of N-pyridyl-Boc-lenalidomide (1 equiv.) in TFA/DCM (1:1) isstirred at rt overnight. Solvent is evaporated and the residue ispurified by column chromatography on silica gel to giveN-pyridyl-lenalidomide.

General Procedure to Prepare O-Aryl Lenalidomide:

General Procedure Example 4: O-Pyridyl-lenalidomide

O-Pyridyl-Boc-lenalidomide

Substituted 2-chloropyridine (1 equiv.), 4-hydroxylenalidomide (1equiv.), and K₃PO₄ (2 equiv.) are introduced under argon in a Schlenktube, equipped with a magnetic stirring bar. The[{Pd(η³-allyl)(μ-Cl)}₂]/ferrocenyl ligand (ratio 1:2, 0.2 mol % Pd)catalyst and toluene are added, and the Schlenk tube is purged severaltimes with argon. The reaction is heated at 115° C. for 20 h. Thesolvent is removed and the residue is purified by column chromatographyon silica gel to give O-pyridyl-Boc-lenalidomide. (Adv. Synth. Catal.2011, 353, 3403-3414)

O-Pyridyl-lenalidomide

A solution of O-pyridyl-Boc-lenalidomide (1 equiv.) in TFA/DCM (1:1) isstirred at rt overnight. Solvent is evaporated and the residue ispurified by column chromatography on silica gel to giveO-pyridyl-lenalidomide.

5-Methylthalidomide Derivatives

4-Methyl-3-nitrophthalic anhydride

Oxidation of ruthenium dioxide to ruthenium tetraoxide is carried outwith aqueous sodium hypochlorite (household bleach, 5.25%concentration). Into a 3-L, three-necked flask fitted with mechanicalstirrer and air condenser are added carbon tetrachloride, RuO₂.H₂O, andbleach. The reaction is stirred until all the insoluble black rutheniumdioxide is converted into soluble yellow ruthenium tetraoxide. As thetwo-phase mixture is being stirred, 1-nitro-2-methylnaphthalene (1equiv.) is added. The reaction is allowed to stir until the black colorof the ruthenium dioxide begins to persist. More bleach is added andstirring is continued. The reaction is then allowed to stir for about 20h. The aqueous phase is separated from the organic layer, concentrated,and extracted with diethyl ether. The ether layer is dried (Na₂SO₄) andconcentrated. The residue is dissolved in ether and filtered, whichleaves behind a large amount of extracted salts. The product in ethersolution is again taken to complete dryness and dissolved in acetone.The acetone solution is concentrated and water is added to retain anyremaining undesired salts. The 4-methyl-3-nitrophthalic acid product isallowed to precipitate from the acetone-water solution.

Excess acetic anhydride is added to 4-methyl-3-nitrophthalic acid. Themixture is heated at gentle reflux until the phthalic acid is completelydissolved. Reflux is continued for an additional 30 min. The reactionmixture is concentrated in vacuo, and the excess acetic anhydride isallowed to evaporate under a gentle stream of dry air to give4-methyl-3-nitrophthalic anhydride. (J. Agric. Food Chem. 1991, 39,554-559)

5-Methyl-4-nitrothalidomide

A mixture of 4-methyl-3-nitrophthalic anhydride (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide 5-methyl-4-nitrothalidomide.

5-Methylpomalidomide

A mixture of 5-methyl-4-nitrothalidomide (1 equiv.) and palladium onactivated carbon (10% wt) in THE is hydrogenated until the disappearanceof the starting material. The mixture is filtered through Celite® andconcentrated to give 5-methylpomalidomide.

General Procedure Example 5: N-linked 5-methylpomalidomide Derivatives

5-Methylpomalidomide (1 equiv.) is dissolved in DMF and K₂CO₃ (2 equiv.)is added, followed by alkyl halides (1.2 equiv.). The mixture is stirredat rt until the consumption of the starting material. The mixture isdiluted with water and extracted with EtOAc. The organic layer is washedwith brine, dried (Na₂SO₄), and concentrated. The residue is purified bycolumn chromatography to give N-linked 5-methylpomalidomide derivatives.

General Procedure Example 6: O-Linked 5-Methylthalidomide Derivatives

15 N Sulfuric acid is cooled to 0° C., 5-methylpomalidomide (1 equiv.)is added gradually with good stirring. After one hour, a solution ofsodium nitrite (1 equiv.) in water is added slowly while maintaining thetemperature below 5° C. After another 30 minutes, the mixture is warmedto 80° C. and maintained at this temperature until nitrogen evolutionceases. The now dark orange solution is diluted with water and extractedwith ether. The organic layer is dried with sodium sulfate, filtered andshaken for two hours with finely powdered barium chloride to removetraces of sulfuric acid. The solution is filtered and concentrated andthe residue is purified by column chromatography to give5-methyl-4-hydroxythalidomide. (J. Am. Chem. Soc., 1955, 77 (19), pp5092-5095)

5-Methyl-4-hydroxythalidomide (1 equiv.) is dissolved in DMF and K₂CO₃(2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixtureis stirred at rt until the consumption of the starting material. Themixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give O-linked5-methylthalidomide derivatives.

6-Methylthalidomide Derivatives

3-Fluoro-5-methylphthalic acid

1,4-Dioxane is added to a mixture of Pd(OAc)₂ (10 mol %),2-fluoro-4-methylbenzoic acid (1 equiv.), Ag₂CO₃ (2 equiv.) and NaOAc (2equiv.) in a Schlenk tube containing a Hi-Vac valve. The Schlenk tube isdegassed under high vacuum and filled with carbon monoxide at roomtemperature. The reaction mixture is heated at 130° C. with vigorousstirring. After 18-48 h, the reaction is cooled to room temperature,acidified with 2 N HCl and thoroughly extracted with ethyl acetate. Theethyl acetate fractions are combined, the solvent is removed in a rotaryevaporator and the product is purified on a silica gel column to provide3-fluoro-5-methylphthalic acid. (J. Am. Chem. Soc., 2008, 130 (43), pp14082-14083)

3-fluoro-5-methylphthalic anhydride

Excess acetic anhydride is added to 3-fluoro-5-methylphthalic acid. Themixture is heated at gentle reflux until the phthalic acid is completelyconsumed. Reflux is continued for an additional 30 min. The reactionmixture is concentrated in vacuo, and the excess acetic anhydride isallowed to evaporate under a gentle stream of dry air to give3-fluoro-5-methylphthalic anhydride. (J. Agric. Food Chem. 1991, 39,554-559)

4-Fluoro-6-methylthalidomide

A mixture of 3-fluoro-5-methylphthalic anhydride (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide 4-fluoro-6-methylthalidomide.

General Procedure Example 7: N-Linked 6-Methylpomalidomide Derivatives

A mixture of 4-fluoro-6-methylthalidomide (1 equiv.), alkyl amine (1equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to provide N-linked6-methylpomalidomide derivatives. (Chem Biol. 2015 Jun. 18;22(6):755-63.)

General Procedure Example 8: O-Linked 6-Methylthalidomide Derivatives

To a cooled solution of alcohol (1.2 equiv.) in DMF is added NaH (1.3equiv.) and stirred at 0° C. for 30 min. 4-Fluoro-6-methylthalidomide (1equiv.) was added and the mixture is heated at 80° C. overnight. Thereaction is cooled and quenched with methanol. The mixture is pouredinto water and extracted with ethyl acetate. The combined organic phasesare washed with water and brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The crude residue is purifiedby column chromatography on silica gel to provide O-linked6-methylthalidomide derivatives.

7-Methylthalidomide Derivatives

3-Fluoro-6-methylphthalic acid

1,4-Dioxane is added to a mixture of Pd(OAc)₂ (10 mol %),2-fluoro-5-methylbenzoic acid (1 equiv.), Ag₂CO₃ (2 equiv.) and NaOAc (2equiv.) in a Schlenk tube containing a Hi-Vac valve. The Schlenk tube isdegassed under high vacuum and filled with carbon monoxide at roomtemperature. The reaction mixture is heated at 130° C. with vigorousstirring. After 18-48 h, the reaction is cooled to room temperature,acidified with 2 N HCl and thoroughly extracted with ethyl acetate. Theethyl acetate fractions are combined, the solvent is removed in a rotaryevaporator and the product is purified on a silica gel column to provide3-fluoro-6-methylphthalic acid. (J. Am. Chem. Soc., 2008, 130 (43), pp14082-14083)

3-Fluoro-6-methylphthalic anhydride

Excess acetic anhydride is added to 3-fluoro-6-methylphthalic acid. Themixture is heated at gentle reflux until the phthalic acid is completelyconsumed. Reflux is continued for an additional 30 min. The reactionmixture is concentrated in vacuo, and the excess acetic anhydride isallowed to evaporate under a gentle stream of dry air to give3-fluoro-6-methylphthalic anhydride. (J. Agric. Food Chem. 1991, 39,554-559)

4-Fluoro-7-methylthalidomide

A mixture of 3-fluoro-6-methylphthalic anhydride (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide 4-fluoro-7-methylthalidomide.

General Procedure Example 9: N-Linked 7-Methylpomalidomide Derivatives

A mixture of 4-fluoro-7-methylthalidomide (1 equiv.), alkyl amine (1equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to provide N-linked7-methylpomalidomide derivatives. (Chem Biol. 2015 Jun. 18;22(6):755-63.)

General Procedure Example 10: O-Linked 7-Methylthalidomide Derivatives

To a cooled solution of alcohol (1.2 equiv.) in DMF is added NaH (1.3equiv.) and stirred at 0° C. for 30 min. 4-Fluoro-7-methylthalidomide (1equiv.) was added and the mixture is heated at 80° C. overnight. Thereaction is cooled and quenched with methanol. The mixture is pouredinto water and extracted with ethyl acetate. The combined organic phasesare washed with water and brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The crude residue is purifiedby column chromatography on silica gel to provide O-linked7-methylthalidomide derivatives.

5-Trifluoromethylthalidomide Derivatives

2-Fluoro-3,4-dimethyl-1-(trifluoromethyl)benzene

An oven-dried vial is equipped with Ru(phen)₃Cl₂ (1-2 mol %), dry K₂HPO₄(3 equiv.), 1-fluoro-2,3-dimethylbenzene (1 equiv.) and MeCN (0.125 M),and degassed by alternating vacuum evacuation and argon backfill at −78°C. The triflyl chloride (1-4 equiv.) is then added and the solution isstirred at room temperature adjacent to a 26-W compact fluorescent lightbulb. After 24 h, the reaction mixture is purified by columnchromatography on silica gel to furnish2-fluoro-3,4-dimethyl-1-(trifluoromethyl)benzene and1-fluoro-2,3-dimethyl-4-(trifluoromethyl)benzene. The former one istaken to proceed to the next steps. (Nature 2011, 480, 224)

3-Fluoro-4-trifluoromethylphthalic acid

2-Fluoro-3,4-dimethyl-1-(trifluoromethyl)benzene (1 equiv.) is dissolvedin acetic acid glacial (0.045 M). To this solution, sulfuric acid about96% is added (1/5 volume of AcOH) and the mixture is cooled toapproximately 15° C. in an ice bath, under stirring. Chromium(VI)trioxide (4.6 equiv.) is added stepwise within approximately 30 min.After the addition, the ice bath is removed and the mixture is allowedto warm to approximately room temperature and then is heated to about35° C. for about 20 h. Further, the mixture is diluted approximately 1.5fold with water and methanol is added cautiously in order to destroy theexcess CrO₃. The aqueous mixture is extracted with ethyl acetate (3×)and the combined organic fractions are washed with water (2×) and driedover Na₂SO₄. After filtration, the solvent is evaporated completelyunder vacuum and the crude is recrystallized from toluene to provide3-fluoro-4-trifluoromethylphthalic acid. (PCT Int. Appl., 2012061344, 10May 2012)

3-Fluoro-4-trifluoromethylphthalic anhydride

Excess acetic anhydride is added to 3-fluoro-4-trifluoromethylphthalicacid. The mixture is heated at gentle reflux until the phthalic acid iscompletely consumed. Reflux is continued for an additional 30 min. Thereaction mixture is concentrated in vacuo, and the excess aceticanhydride is allowed to evaporate under a gentle stream of dry air togive 3-fluoro-4-trifluoromethylphthalic anhydride. (J. Agric. Food Chem.1991, 39, 554-559)

4-Fluoro-5-trimethylfluorothalidomide

A mixture of 3-fluoro-4-trifluoromethylphthalic anhydride (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide4-fluoro-5-trimethylfluorothalidomide.

General Procedure Example 11: N-Linked 5-TrimethylfluoropomalidomideDerivatives

A mixture of 4-fluoro-5-trimethylfluorothalidomide (1 equiv.), alkylamine (1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for12 h. The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to provide N-linked5-trimethylfluoropomalidomide derivatives. (Chem Biol. 2015 Jun. 18;22(6):755-63.)

General Procedure Example 12: O-Linked 5-TrimethylfluorothalidomideDerivatives

To a cooled solution of alcohol (1.2 equiv.) in DMF is added NaH (1.3equiv.) and stirred at 0° C. for 30 min.4-fluoro-5-trimethylfluorothalidomide (1 equiv.) was added and themixture is heated at 80° C. overnight. The reaction is cooled andquenched with methanol. The mixture is poured into water and extractedwith ethyl acetate. The combined organic phases are washed with waterand brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The crude residue is purified by column chromatographyon silica gel to provide O-linked 5-trimethylfluorothalidomidederivatives.

6-Trifluoromethylthalidomide Derivatives

1,2-Dimethyl-3-nitro-5-(trifluoromethyl)benzene

In particular, a mixture of sulfuric acid about 96% (42 equiv.) andfuming nitric acid (14 equiv.) is given under stirring to1,2-dimethyl-4-(trifluoromethyl)benzene (1 equiv.) and heated toapproximately 60° C. for about 3 h. After cooling to room temperature,the mixture is poured over crushed ice. The milky solution is thenextracted with CH₂Cl₂ (2×). The combined organic fractions are washedwith 3% Na₂CO₃ solution (2×) and then water (2×). The organic solutionis dried over Na₂SO₄, filtered and evaporated in vacuo. The crude ispurified by column chromatography on silica gel to give1,2-dimethyl-3-nitro-5-(trifluoromethyl)benzene. (PCT Int. Appl.,2012061344, 10 May 2012)

3-Nitro-5-trifluoromethylphthalic acid

1,2-dimethyl-3-nitro-5-(trifluoromethyl)benzene (1 equiv.) is dissolvedin acetic acid glacial (0.045 M). To this solution, sulfuric acid about96% is added (1/5 volume of AcOH) and the mixture is cooled toapproximately 15° C. in an ice bath, under stirring. Chromium(VI)trioxide (4.6 equiv.) is added stepwise within approximately 30 min.After the addition, the ice bath is removed and the mixture is allowedto warm to approximately room temperature and then is heated to about35° C. for about 20 h. Further, the mixture is diluted approximately 1.5fold with water and methanol is added cautiously in order to destroy theexcess CrO₃. The aqueous mixture is extracted with ethyl acetate (3×)and the combined organic fractions are washed with water (2×) and driedover Na₂SO₄. After filtration, the solvent is evaporated completelyunder vacuum and the crude is recrystallized from toluene to provide3-nitro-5-trifluoromethylphthalic acid. (PCT Int. Appl., 2012061344, 10May 2012)

3-Nitro-5-trifluoromethylphthalic anhydride

Excess acetic anhydride is added to 3-nitro-5-trifluoromethylphthalicacid. The mixture is heated at gentle reflux until the phthalic acid iscompletely consumed. Reflux is continued for an additional 30 min. Thereaction mixture is concentrated in vacuo, and the excess aceticanhydride is allowed to evaporate under a gentle stream of dry air togive 3-nitro-5-trifluoromethylphthalic anhydride. (J. Agric. Food Chem.1991, 39, 554-559)

4-Nitro-6-trimethylfluorothalidomide

A mixture of 3-nitro-5-trifluoromethylphthalic anhydride (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide4-nitro-6-trimethylfluorothalidomide.

4-Amino-6-trimethylfluorothalidomide

A mixture of 4-nitro-6-trimethylfluorothalidomide (1 equiv.) andpalladium on activated carbon (10% wt) in THE is hydrogenated until thedisappearance of the starting material. The mixture is filtered throughCelite® and concentrated to give 4-amino-6-trimethylfluorothalidomide.

General Procedure Example 13: N-Linked 6-TrimethylfluoropomalidomideDerivatives

4-Amino-6-trimethylfluorothalidomide (1 equiv.) is dissolved in DMF andK₂CO₃ (2 equiv.) is added, followed by alkyl halides (1.2 equiv.). Themixture is stirred at rt until the consumption of the starting material.The mixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give N-linked6-trimethylfluoropomalidomide derivatives.

General Procedure Example 14: O-Linked 6-TrifluoromethylthalidomideDerivatives

15 N Sulfuric acid is cooled to 0° C.,4-amino-6-trimethylfluorothalidomide (1 equiv.) is added gradually withgood stirring. After one hour, a solution of sodium nitrite (1 equiv.)in water is added slowly while maintaining the temperature below 5° C.After another 30 minutes, the mixture is warmed to 80° C. and maintainedat this temperature until nitrogen evolution ceases. The now dark orangesolution is diluted with water and extracted with ether. The organiclayer is dried with sodium sulfate, filtered and shaken for two hourswith finely powdered barium chloride to remove traces of sulfuric acid.The solution is filtered and concentrated and the residue is purified bycolumn chromatography to give 4-hydroxy-6-trimethylfluorothalidomide.(J. Am. Chem. Soc., 1955, 77 (19), pp 5092-5095)

4-hydroxy-6-trimethylfluorothalidomide (1 equiv.) is dissolved in DMFand K₂CO₃ (2 equiv.) is added, followed by alkyl halides (1.2 equiv.).The mixture is stirred at rt until the consumption of the startingmaterial. The mixture is diluted with water and extracted with EtOAc.The organic layer is washed with brine, dried (Na₂SO₄), andconcentrated. The residue is purified by column chromatography to giveO-linked 6-trifluoromethylthalidomide derivatives.

7-Trifluoromethylthalidomide Derivatives

1-Fluoro-2,3-dimethyl-4-(trifluoromethyl)benzene

An oven-dried vial is equipped with Ru(phen)₃Cl₂ (1-2 mol %), dry K₂HPO₄(3 equiv.), 1-fluoro-2,3-dimethylbenzene (1 equiv.) and MeCN (0.125 M),and degassed by alternating vacuum evacuation and argon backfill at −78°C. The triflyl chloride (1-4 equiv.) is then added and the solution isstirred at room temperature adjacent to a 26-W compact fluorescent lightbulb. After 24 h, the reaction mixture is purified by columnchromatography on silica gel to furnish2-fluoro-3,4-dimethyl-1-(trifluoromethyl)benzene and1-fluoro-2,3-dimethyl-4-(trifluoromethyl)benzene. The latter one istaken to proceed to the next steps. (Nature 2011, 480, 224).

3-Fluoro-6-trifluoromethylphthalic acid

1-fluoro-2,3-dimethyl-4-(trifluoromethyl)benzene (1 equiv.) is dissolvedin acetic acid glacial (0.045 M). To this solution, sulfuric acid about96% is added (1/5 volume of AcOH) and the mixture is cooled toapproximately 15° C. in an ice bath, under stirring. Chromium(VI)trioxide (4.6 equiv.) is added stepwise within approximately 30 min.After the addition, the ice bath is removed and the mixture is allowedto warm to approximately room temperature and then is heated to about35° C. for about 20 h. Further, the mixture is diluted approximately 1.5fold with water and methanol is added cautiously in order to destroy theexcess CrO₃. The aqueous mixture is extracted with ethyl acetate (3×)and the combined organic fractions are washed with water (2×) and driedover Na₂SO₄. After filtration, the solvent is evaporated completelyunder vacuum and the crude is recrystallized from toluene to provide3-fluoro-6-trifluoromethylphthalic acid. (PCT Int. Appl., 2012061344, 10May 2012)

3-Fluoro-6-trifluoromethylphthalic anhydride

Excess acetic anhydride is added to 3-fluoro-6-trifluoromethylphthalicacid. The mixture is heated at gentle reflux until the phthalic acid iscompletely consumed. Reflux is continued for an additional 30 min. Thereaction mixture is concentrated in vacuo, and the excess aceticanhydride is allowed to evaporate under a gentle stream of dry air togive 3-fluoro-6-trifluoromethylphthalic anhydride. (J. Agric. Food Chem.1991, 39, 554-559).

4-Fluoro-7-trimethylfluorothalidomide

A mixture of 3-fluoro-6-trifluoromethylphthalic anhydride (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide4-fluoro-7-trimethylfluorothalidomide.

General Procedure Example 15: N-Linked 7-TrimethylfluoropomalidomideDerivatives

A mixture of 4-fluoro-7-trimethylfluorothalidomide (1 equiv.), alkylamine (1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for12 h. The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to provide N-linked7-trimethylfluoropomalidomide derivatives. (Chem Biol. 2015 Jun. 18;22(6):755-63.)

General Procedure Example 16: O-Linked 7-TrimethylfluorothalidomideDerivatives

To a cooled solution of alcohol (1.2 equiv.) in DMF is added NaH (1.3equiv.) and stirred at 0° C. for 30 min.4-fluoro-7-trimethylfluorothalidomide (1 equiv.) was added and themixture is heated at 80° C. overnight. The reaction is cooled andquenched with methanol. The mixture is poured into water and extractedwith ethyl acetate. The combined organic phases are washed with waterand brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The crude residue is purified by column chromatographyon silica gel to provide O-linked 7-trimethylfluorothalidomidederivatives.

5,6,7-Hydroxythalidomide/pomalidomide

5,6,7-hydroxypomalidomide and intermediates were reported in Celgenepatent (WO-2014018866-A1):

5,6,7-Alkoxythalidomide/pomalidomide

Starting materials are found in Celgene patent (WO-2014018866-A1)

N-Linked 5-alkoxypomalidomide

O-Linked 5-alkoxythalidomide

N-Linked 6-alkoxypomalidomide

O-Linked 6-alkoxythalidomide

N-Linked 7-alkoxypomalidomide

O-Linked 7-alkoxythalidomide

General Procedure Example 17: N-Linked 5-Alkoxypomalidomide Derivatives5-Alkoxy-4-nitrothalidomide

5-hydroxy-4-nitrothalidomide (1 equiv.) is dissolved in DMF and K₂CO₃ (2equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture isstirred at rt until the consumption of the starting material. Themixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give5-alkoxy-4-nitrothalidomide.

4-Amino-5-alkoxythalidomide

A mixture of 5-alkoxy-4-nitrothalidomide (1 equiv.) and palladium onactivated carbon (10% wt) in THE is hydrogenated until the disappearanceof the starting material. The mixture is filtered through Celite® andconcentrated to give 4-amino-5-alkoxythalidomide.

N-Linked 5-alkoxypomalidomide Derivatives

4-amino-5-alkoxythalidomide (1 equiv.) is dissolved in DMF and K₂CO₃ (2equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture isstirred at rt until the consumption of the starting material. Themixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give N-linked5-alkoxypomalidomide derivatives.

General Procedure Example 18: O-Linked 5-Alkoxythalidomide Derivatives

4-Hydroxy-5-methoxythalidomide

15 N Sulfuric acid is cooled to 0° C., 4-amino-5-methoxythalidomide (1equiv.) is added gradually with good stirring. After one hour, asolution of sodium nitrite (1 equiv.) in water is added slowly whilemaintaining the temperature below 5° C. After another 30 minutes, themixture is warmed to 80° C. and maintained at this temperature untilnitrogen evolution ceases. The now dark orange solution is diluted withwater and extracted with ether. The organic layer is dried with sodiumsulfate, filtered and shaken for two hours with finely powdered bariumchloride to remove traces of sulfuric acid. The solution is filtered andconcentrated and the residue is purified by column chromatography togive 4-hydroxy-5-methoxythalidomide.

4-Alkoxy-5-methoxythalidomide

4-Hydroxy-5-methoxythalidomide (1 equiv.) is dissolved in DMF and K₂CO₃(2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixtureis stirred at rt until the consumption of the starting material. Themixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give4-alkoxy-5-methoxythalidomide.

4-Alkoxy-5-hydroxythalidomide

To a solution of 4-alkoxy-5-methoxythalidomide (1 equiv.) in DCM isadded BBr₃ (10 equiv.). The mixture is stirred at rt for 12 h. Thereaction is quenched by adding DCM and water. The organic layer isseparated, dried over sodium sulfate, filtered, and concentrated. Theresidue is purified by column chromatography to give4-alkoxy-5-hydroxythalidomide.

O-Linked 5-Alkoxythalidomide Derivatives

4-Alkoxy-5-hydroxythalidomide (1 equiv.) is dissolved in DMF and K₂CO₃(2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixtureis stirred at rt until the consumption of the starting material. Themixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give O-linked5-alkoxythalidomide derivatives.

Thal/Pom/Len Analogs with Variation on the Glutarimide Moiety

α-Fluoro, Methyl, Deutero-Substituted Thalidomide/Pomalidomide

General Procedure Example 19: N-Linked a-D Pomalidomide Derivatives

α-D N-Boc-pomalidomide

A mixture of α-D N-Boc-4-nitrothalidomide (known compound reported inBMCL, 2003, 13, 3415) (1 equiv.) and palladium on activated carbon (10%wt) in THF is hydrogenated until the disappearance of the startingmaterial. The mixture is filtered through Celite® and concentrated togive α-D N-Boc-pomalidomide.

N-Linked α-D Pomalidomide Derivatives

α-D N-Boc-pomalidomide (1 equiv.) is dissolved in DMF and K₂CO₃ (2equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture isstirred at rt until the consumption of the starting material. Themixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give α-DN-Boc-pomalidomide derivatives.

A solution of α-D N-Boc-pomalidomide derivatives (1 equiv.) in TFA/DCM(1:1) is stirred at rt overnight. Solvent is evaporated and the residueis purified by column chromatography on silica gel to give N-linked α-Dpomalidomide derivatives.

General Procedure Example 20: O-Linked α-D Thalidomide Derivatives

α-D N-Boc-4-hydroxythalidomide

15 N Sulfuric acid is cooled to 0° C., α-D N-Boc-pomalidomide (1 equiv.)is added gradually with good stirring. After one hour, a solution ofsodium nitrite (1 equiv.) in water is added slowly while maintaining thetemperature below 5° C. After another 30 minutes, the mixture is warmedto 80° C. and maintained at this temperature until nitrogen evolutionceases. The now dark orange solution is diluted with water and extractedwith ether. The organic layer is dried with sodium sulfate, filtered andshaken for two hours with finely powdered barium chloride to removetraces of sulfuric acid. The solution is filtered and concentrated andthe residue is purified by column chromatography to give α-DN-Boc-4-hydroxythalidomide.

O-Linked α-D Thalidomide Derivatives

α-D N-Boc-4-hydroxythalidomide (1 equiv.) is dissolved in DMF and K₂CO₃(2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixtureis stirred at rt until the consumption of the starting material. Themixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give α-DN-Boc-4-hydroxythalidomide derivatives.

A solution of α-D N-Boc-4-hydroxythalidomide derivatives (1 equiv.) inTFA/DCM (1:1) is stirred at rt overnight. Solvent is evaporated and theresidue is purified by column chromatography on silica gel to giveO-linked α-D thalidomide derivatives.

General Procedure Example 21: N-Linked α-F Pomalidomide Derivatives

α-F N-Boc-pomalidomide (known compound reported in BMCL, 2003, 13, 3415)(1 equiv.) is dissolved in DMF and K₂CO₃ (2 equiv.) is added, followedby alkyl halides (1.2 equiv.). The mixture is stirred at rt until theconsumption of the starting material. The mixture is diluted with waterand extracted with EtOAc. The organic layer is washed with brine, dried(Na₂SO₄), and concentrated. The residue is purified by columnchromatography to give α-F N-Boc-pomalidomide derivatives.

A solution of α-F N-Boc-pomalidomide derivatives (1 equiv.) in TFA/DCM(1:1) is stirred at rt overnight. Solvent is evaporated and the residueis purified by column chromatography on silica gel to give N-linked α-Fpomalidomide derivatives.

General Procedure Example 22: O-Linked α-F Thalidomide Derivatives

α-F N-Boc-4-hydroxythalidomide

15 N Sulfuric acid is cooled to 0° C., α-F N-Boc-pomalidomide (1 equiv.)is added gradually with good stirring. After one hour, a solution ofsodium nitrite (1 equiv.) in water is added slowly while maintaining thetemperature below 5° C. After another 30 minutes, the mixture is warmedto 80° C. and maintained at this temperature until nitrogen evolutionceases. The now dark orange solution is diluted with water and extractedwith ether. The organic layer is dried with sodium sulfate, filtered andshaken for two hours with finely powdered barium chloride to removetraces of sulfuric acid. The solution is filtered and concentrated andthe residue is purified by column chromatography to give α-FN-Boc-4-hydroxythalidomide.

O-Linked α-F Thalidomide Derivatives

α-F N-Boc-4-Hydroxythalidomide (1 equiv.) is dissolved in DMF and K₂CO₃(2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixtureis stirred at rt until the consumption of the starting material. Themixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography to give α-FN-Boc-4-hydroxythalidomide derivatives.

A solution of α-F N-Boc-4-hydroxythalidomide derivatives (1 equiv.) inTFA/DCM (1:1) is stirred at rt overnight. Solvent is evaporated and theresidue is purified by column chromatography on silica gel to giveO-linked α-F thalidomide derivatives.

General Procedure Example 23: N-Linked α-Methylpomalidomide Derivatives

N-Boc 4-Fluorothalidomide

To a stirred solution of 4-fluorothalidomide (1.0 equiv.) in DMF isadded potassium carbonate (2.0 equiv.). The resulting solution is cooledto 0-5° C. and Boc anhydride (3.0 equiv.) is added slowly as a solutionin 1,4-dioxane (also cooled). The resulting mixture is stirred at 0° C.for 1 h and allowed to warm to room temperature overnight. Water is thenadded and the aqueous layer is extracted 2 times with DCM andconcentrated. The residue is purified by column chromatography on silicagel to obtain N-Boc 4-fluorothalidomide.

N-Boc 4-Fluoro-α-methylthalidomide

To a solution of N-Boc 4-fluorothalidomide (1 equiv.) in DMF is addedsodium hydride (2 equiv.) slowly at 0° C. The mixture is stirred at 0°C. for 30 min and methyl iodide (1.1 equiv.) is added dropwise. Themixture is stirred at rt until the consumption of the starting materialand then quenched with methanol. The mixture is diluted with saturatedNaHCO₃, extracted with EtOAc, dried (Na₂SO₄), and concentrated. Theresidue is purified by column chromatography on silica gel to obtainN-Boc 4-fluoro-α-methylthalidomide.

N-Linked α-Methylpomalidomide Derivatives

A mixture of N-Boc 4-fluoro-α-methylthalidomide (1 equiv.), alkyl amine(1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to provide N-Boca-methylpomalidomide derivatives. (ref: Chem Biol. 2015 Jun. 18;22(6):755-63.) A solution of N-Boc α-methylpomalidomide derivatives (1equiv.) in TFA/DCM (1:1) is stirred at rt overnight. Solvent isevaporated and the residue is purified by column chromatography onsilica gel to give N-linked α-methylpomalidomide derivatives.

5′-Hydroxyl, Alkoxy, Amino, Sulfonamide Substituted Glutarimide

General Procedure Example 24: 5′-Hydroxyl Substituted PomalidomideDerivatives

5′-tert-Butyldimethylsilyloxy-4-fluorothalidomide

A mixture of3-amino-5-((tert-butyldimethylsilyl)oxy)piperidine-2,6-dione (knowncompound reported in Chem. Pharm. Bull. 2006, 54, 1709) (1 equiv.),3-aminopiperidine-2,6-dione HCl salt (1 equiv.), and potassium acetate(2.5 equiv.) in acetic acid is stirred at 120° C. overnight. The darkmixture is cooled and filtered. The filter cake is dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide5′-tert-butyldimethylsilyloxy-4-fluorothalidomide.

5′-Tert-Butyldimethylsilyloxy-Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),5′-tert-butyldimethylsilyloxy-4-fluorothalidomide (1 equiv.) and DIEA (2equiv.) in dry DMF is stirred at 90° C. for 12 h. The mixture is cooledto room temperature, poured into water and extracted with ethyl acetate.The combined organic phases are washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Thecrude residue is purified by column chromatography on silica gel to give5′-tert-butyldimethylsilyloxy-pomalidomide derivatives. (Chem Biol. 2015Jun. 18; 22(6):755-63.)

5′-Hydroxyl Pomalidomide Derivatives

To a solution of 5′-tert-butyldimethylsilyloxy-pomalidomide derivatives(1 equiv.) in dry THE is added TBAF (1.1 equiv.) at 0° C., and thereaction mixture is stirred at 0° C. for 40 min, and then at roomtemperature for 2 h. CHCl₃ is added, and the mixture is washed with 0.5M HCl and brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct is purified by flash column chromatography on silica gel toprovide 5′-hydroxyl pomalidomide derivatives. (Chem. Pharm. Bull. 2006,54, 1709)

General Procedure Example 25: 5′-Alkoxy Substituted PomalidomideDerivatives

To a solution of 5′-hydroxyl pomalidomide derivatives (1 equiv.) andalkyl halide (2 eq.) in Et₂O (0.05 M) under a nitrogen atmosphere isadded Ag₂0 (2 equiv.) at room temperature. The resulting suspension isstirred at dark at room temperature for 16 h then filtered through a padof Celite® using Et₂O as eluent. The residue is concentrated in vacuoand purified by column chromatography on silica gel to provide 5′-alkoxypomalidomide derivatives. (Org. Lett. 2013, 15, 5878)

General Procedure Example 26: 5′-Amino Substituted PomalidomideDerivatives

5′-Azido Pomalidomide Derivatives

5′-Hydroxy pomalidomide derivatives (1 equiv.) is dissolved in anhydrous1,4-dioxane under nitrogen. 1.4 M n-butyllithium hexane solution (5equiv.) diluted with 1,4-dioxane is added, and stirred for 10 minutes atroom temperature. A solution of p-toluene sulfonyl chloride in1,4-dioxane is added and stirred for 1 hour. After reaction completion,it is quenched with aqueous ammonia chloride, and extracted with EtOAc.The organic layer is dried (Na₂SO₄) and concentrated to provide5′-tosyloxy-pomalidomide derivatives, which are used in next reactionwithout further purification. (Jpn. Kokai Tokkyo Koho, 2009215195, 24Sep. 2009)

To a stirred solution of 5′-tosyloxy-pomalidomide derivatives (1 equiv.)in anhydrous DMF at 70° C. under a N₂ atmosphere is added NaN₃ (5equiv.). The mixture is then allowed to stir at 70° C. for 6 h, and thenquenched with cool H₂O and extracted with EtOAc (2×). The combinedorganic extracts are washed with cool H₂O and brine, dried (Na₂SO₄), andconcentrated and purified by flash column chromatography on silica gelto provide 5′-azido pomalidomide derivatives. (Synthesis 2013, 45,3383-3386)

5′-Amino Pomalidomide Derivatives

A mixture of azide (1 equiv.) and Pd/C 10% w/w in MeOH is stirred underhydrogen for 8 h. The mixture is then filtered and concentrated to givethe crude amine, which is purified by flash column chromatography onsilica gel to give 5′-amino pomalidomide derivatives.

General Procedure Example 27: 5′-Sulfonamide Substituted Pomalidomide

To a solution of 5′-amino pomalidomide derivatives (1 equiv.),triethylamine (2 equiv.) in chloroform is added sulfonyl chloride (1.1equiv.). The reaction is stirred till the consumption of the startingmaterial. The mixture is then extracted with EtOAc, washed with waterand brine, dried (Na₂SO₄), and concentrated. The residue is purified byflash column chromatography on silica gel to give 5′-sulfonamidepomalidomide derivatives.

5′,5′-Difluoro Substituted Glutarimide

General Procedure Example 28: 5′,5′-Difluoro Substituted PomalidomideDerivatives

N-Boc-4,4-Difluoropyroglutamic acid

To a stirred solution of 4,4-difluoropyroglutamic acid (known compoundreported in Org. Lett. 1999, 1, 2105) (1.0 equiv.) in DMF is added Bocanhydride (2.0 equiv.), followed by DMAP (0.1 equiv.). The resultingmixture is stirred at room temperature overnight. Water is then addedand the aqueous layer is extracted 2 times with DCM and concentrated.The residue is purified by column chromatography on silica gel to obtainN-Boc-4,4-difluoropyroglutamic acid.

N-Boc-4,4-Difluoropyroglutamide

To a solution of N-Boc-4,4-difluoropyroglutamic acid (1 equiv.) in dryCH₃CN is added EDCI.HCl (1.2 equiv.) and HOBT (1.2 equiv.) at 0° C. Themixture is stirred at room temperature for 6 h, then cooled to 0° C.,and 28% aqueous ammonia (excess) is carefully added. Stirring iscontinued at 0° C. for 30 min and then at room temperature for 1 h.Insoluble material is removed by filtration, then the filtrate wasconcentrated and purified by flash column chromatography on silica gelto provide N-Boc-4,4-difluoropyroglutamide. (Chem. Pharm. Bull. 2006,54, 1709).

3-N-Boc-Amino-5,5-difluoroglutarimide

A solution of N-Boc-4,4-difluoropyroglutamide (1 equiv.) in dry THE isstirred at 0° C., and 1.0 M aqueous LiOH (3 equiv.) is carefully added.The reaction mixture is stirred at 0° C. for 3 h, then acidified byaddition of 2.0 M aqueous HCl, and extracted 3 times with CHCl₃. Theorganic layer is washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford5-amino-4-(N-Boc-amino)-2,2-difluoro-5-oxopentanoic acid, which is useddirectly for the next step without further purification.

To a solution of 5-amino-4-(N-Boc-amino)-2,2-difluoro-5-oxopentanoicacid (1 equiv.) in dry DCM is added CDI (1.15 equiv.), DMAP (0.1equiv.), and DIPEA (2 equiv.) at 0° C. The mixture is stirred at roomtemperature for 5 d, then washed with 0.5 M aqueous HCl and brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash column chromatography on silica gel to provide3-N-Boc-amino-5,5-difluoroglutarimide. (Chem. Pharm. Bull. 2006, 54,1709)

3-Amino-5,5-difluoroglutarimide

A solution of 3-N-Boc-amino-5,5-difluoroglutarimide (1 equiv.) inTFA/DCM (1:1) is stirred at rt overnight. Solvent is evaporated and theresidue is purified by column chromatography on silica gel to give3-amino-5,5-difluoroglutarimide.

5′,5′-Difluoro-4-fluorothalidomide

A mixture of 3-fluorophthalic anhydride (1 equiv.),3-amino-5,5-difluoroglutarimide (1 equiv.), and potassium acetate (2.5equiv.) in acetic acid is stirred at 120° C. overnight. The dark mixtureis cooled and filtered. The filter cake is dissolved in DCM and washedwith saturated NaHCO₃ and brine. The organic layer is dried (Na₂SO₄) andconcentrated to provide 5′,5′-difluoro-4-fluorothalidomide.

5′,5′-Difluoro Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.), 5′,5′-difluoro-4-fluorothalidomide(1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to give 5′,5′-difluoro pomalidomidederivatives. (Chem Biol. 2015, 22, 755-763)

Oxetano Glutarimide

2′-Oxetanothalidomide/lenalidomide were reported by Erick M. Carreira(Org. Lett. 2013, 15, 4312)

6′-Oxetanothalidomide/pomalidomide/lenalidomide

General Procedure Example 29: 6′-Oxetanopomalidomide

Ethyl 3-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)propiolate

Known compound and procedure reported in Org. Lett. 2010, 12, 1116.

2-Methyl-N-(3-(3-oxopropyl)oxetan-3-yl)propane-2-sulfinamide

To a solution of ethyl3-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)propiolate (1 equiv.) inEtOAc is added PtO₂/C (0.1 wt equiv.). The reaction vessel is purgedthree times with hydrogen and heated under hydrogen until theconsumption of starting material. Upon cooling to ambient temperature,the reaction mixture is filtered through Celite® and concentrated togive ethyl 3-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)propanoate, whichis used directly without further purifications.

The ester obtained above is dissolved in THF, and cooled to −78° C.DIBAL (1.0 equiv.) is added carefully while monitoring the conversion ofthe starting material. When considerable amount of aldehyde is formed,the reaction is quenched with saturated ammonium chloride, extractedwith EtOAc, washed with brine, dried over sodium sulfate, andconcentrated. The aldehyde is used directly or purified by columnchromatography.

N-(3-(3-Amino-3-cyanopropyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide

To a mixture of magnesium sulfate (0.5 equiv.), ammonium chloride (0.5equiv.), and sodium cyanide (1 equiv.) is added 7 M ammonia in methanol(4 equiv.). The mixture is stirred and cooled to 0° C. After 10 min, theresulting suspension is added to aldehyde (1 equiv.). The mixture isstirring for 1 h at 0° C., then increased to RT and continued to reactfor 4 h. The solvent is then removed under reduced pressure whilemaintaining the internal temperature <30° C. until nearly all of themethanol and ammonia are removed. The resulting slurry of inorganicsalts and the product is diluted with MTBE, stirred at RT for 30 min,and filtered. The inorganic wet cake is washed with MTBE, and thesolvent is removed under reduced pressure to provideN-(3-(3-amino-3-cyanopropyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide.(ACS Med. Chem. Lett. 2014, 5, 1152-1155).

2-Amino-4-(3-aminooxetan-3-yl)butanoic acid

N-(3-(3-amino-3-cyanopropyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide(1 equiv.) is dissolve in 12 M HCl (excess) and stirred for 48 hours at100° C. in a closed vial. Solvent is then removed in vacuo to provide2-amino-4-(3-aminooxetan-3-yl)butanoic acid. (Angew. Chem. Int. Ed.2014, 53, 557)

7-Amino-2-oxa-5-azaspiro[3.5]nonan-6-one

A mixture of 2-amino-4-(3-aminooxetan-3-yl)butanoic acid (1 equiv.),alumina (3 wt. equiv.) in toluene is heated under reflux for 1.5 h. Thewater produced during the reaction is collected in a Dean-Stark trap.The reaction mixture is allowed to cool and the alumina is filtered offand washed with 10% MeOH/CH₂Cl₂. The filtration is combined and thesolvent is removed under vacuum to provide7-amino-2-oxa-5-azaspiro[3.5]nonan-6-one. (Org. Biomol. Chem. 2015, 13,7624-7627)

4-Fluoro-6′-oxetano-thalidomide

A mixture of 3-fluorophthalic anhydride (1 equiv.),7-amino-2-oxa-5-azaspiro[3.5]nonan-6-one (1 equiv.), and potassiumacetate (2.5 equiv.) in acetic acid is stirred at 120° C. overnight. Thedark mixture is cooled and filtered. The filter cake is dissolved in DCMand washed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide 4-fluoro-6′-oxetano-thalidomide.

6′-Oxetano-Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.), 4-fluoro-6′-oxetano-thalidomide (1equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to give 6′-oxetano-pomalidomidederivatives. (Chem Biol. 2015, 22, 755-763).

6′-Sulfonyl glutarimide

General Procedure Example 30: 6′-Sulfonyl Pomalidomide Derivatives

Ethyl 2-nitro-4-(phenoxysulfonyl)butanoate

A mixture of ethyl 2-nitroacetate (2 equiv.), potassium carbonate (1equiv.) and 18-crown-6 (0.5 equiv.) in toluene is heated to 90° C. andphenyl vinylsulfonate (1 equiv.) in toluene is added dropwise over onehour. The mixture is heated for 16 hours, cooled to ambient temperatureand diluted with ethyl acetate. The mixture is washed with saturatedbrine. The organic layer is separated and the aqueous layer is extractedwith ethyl acetate. The combined organic layers are dried (Na₂SO₄),filtered and concentrated in vacuo. The residue is purified by columnchromatography on silica gel to give ethyl2-nitro-4-(phenoxysulfonyl)butanoate. (PCT Int. Appl., 2000006537, 10Feb. 2000)

2-Nitro-4-(phenoxysulfonyl)butanoic acid

A mixture of 2-nitro-4-(phenoxysulfonyl)butanoate (1 equiv.), 1 M NaOH(excess) in methanol is stirred at rt for 2 h. The reaction isneutralized with 1 M HCl and concentrated to provide2-nitro-4-(phenoxysulfonyl)butanoic acid.

Phenyl 4-amino-3-nitro-4-oxobutane-1-sulfonate

To a solution of 2-nitro-4-(phenoxysulfonyl)butanoic acid (1 equiv.) indry CH₃CN is added EDCI.HCl (1.2 equiv.) and HOBT (1.2 equiv.) at 0° C.The mixture is stirred at room temperature for 6 h, then cooled to 0°C., and 28% aqueous ammonia (excess) is carefully added. Stirring iscontinued at 0° C. for 30 min and then at room temperature for 1 h.Insoluble material is removed by filtration, then the filtrate wasconcentrated and purified by flash column chromatography on silica gelto provide phenyl 4-amino-3-nitro-4-oxobutane-1-sulfonate. (Chem. Pharm.Bull. 2006, 54, 1709)

4-Nitro-1,2-thiazinan-3-one 1,1-dioxide

To a 0° C. solution of 1.0 M THE solution of potassium tert-butoxide (2equiv.) in THE is added a solution of4-amino-3-nitro-4-oxobutane-1-sulfonate (1 equiv.) in THE dropwise over30 minutes. After stirring at 0° C. for 2 h, the cooling bath is removedand stirring continued for 30 minutes. The mixture is diluted with waterand extracted two times with ethyl ether. The aqueous portion isacidified to pH 2 with 10% aqueous sodium bisulfate and extracted fourtimes with 20 mL each of ethyl acetate. The combined ethyl acetatelayers are dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue is purified by column chromatography on silica gel to give4-nitro-1,2-thiazinan-3-one 1,1-dioxide. (PCT Int. Appl., 2000006537, 10Feb. 2000)

4-Amino-1,2-thiazinan-3-one 1,1-dioxide

A mixture of 4-nitro-1,2-thiazinan-3-one 1,1-dioxide (1 equiv.) andpalladium on activated carbon (10% wt) in THE is hydrogenated until thedisappearance of the starting material. The mixture is filtered throughCelite® and concentrated to give 4-amino-1,2-thiazinan-3-one1,1-dioxide.

4-Fluoro-6′-sulfonyl-thalidomide

A mixture of 3-fluorophthalic anhydride (1 equiv.),4-amino-1,2-thiazinan-3-one 1,1-dioxide (1 equiv.), and potassiumacetate (2.5 equiv.) in acetic acid is stirred at 120° C. overnight. Thedark mixture is cooled and filtered. The filter cake is dissolved in DCMand washed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide 4-fluoro-6′-sulfonyl-thalidomide.

6′-Sulfonyl Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.), 4-fluoro-6′-sulfonyl-thalidomide (1equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to give 6′-sulfonyl pomalidomidederivatives. (Chem Biol. 2015, 22, 755-763)

2′-Sulfonyl glutarimide

General Procedure Example 31: 2′-Sulfonyl Pomalidomide Derivatives

Phenyl nitromethanesulfonate

To a dry THE solution containing phenyl methanesulfonate (1 equiv.) at−10° C. under a nitrogen atmosphere is added dropwise 1.6 M n-BuLi inhexane (2.4 equiv.). The mixture is stirred for 10 min, and then cooledto −30° C. and isoamylnitrate (2.2 equiv.) is then added dropwise. Afterstirring for 4 h at the same temperature, the reaction is quenched withwater, and the volatiles are evaporated in vacuo. 1 M NaOH (2 equiv.) isadded to the reaction mixture and the mixture is washed with ethylether. The aqueous layer is acidified with acetic acid (pH=5), andextracted with CH₂Cl₂. The organic layer is washed with brine and driedover anhydrous Na₂SO₄, filtered, and concentrated. The residue ispurified by column chromatography on silica gel to provide phenylnitromethanesulfonate. (Bioorg. Med. Chem. 2000, 8, 2167-2173)

Phenyl 4-amino-1-nitro-4-oxobutane-1-sulfonate

A mixture of phenyl nitromethanesulfonate (1 equiv.), potassiumcarbonate (1 equiv.) and 18-crown-6 (0.5 equiv.) in toluene is stirredand acrylamide (1 equiv.) is added dropwise. The mixture is stirred for16 hours, and diluted with ethyl acetate. The mixture is washed withsaturated brine. The organic layer is separated and the aqueous layer isextracted with ethyl acetate. The combined organic layers are dried(Na₂SO₄), filtered and concentrated in vacuo. The residue is purified bycolumn chromatography on silica gel to give phenyl4-amino-1-nitro-4-oxobutane-1-sulfonate.

6-Nitro-1,2-thiazinan-3-one 1,1-dioxide

To a 0° C. solution of 1.0 M THE solution of potassium tert-butoxide (2equiv.) in THE is added a solution of phenyl4-amino-1-nitro-4-oxobutane-1-sulfonate (1 equiv.) in THE dropwise over30 minutes. After stirring at 0° C. for 2 h, the cooling bath is removedand stirring continued for 30 minutes. The mixture is diluted with waterand extracted two times with ethyl ether. The aqueous portion isacidified to pH 2 with 10% aqueous sodium bisulfate and extracted fourtimes with 20 mL each of ethyl acetate. The combined ethyl acetatelayers are dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue is purified by column chromatography on silica gel to give6-nitro-1,2-thiazinan-3-one 1,1-dioxide. (PCT Int. Appl., 2000006537, 10Feb. 2000)

6-Amino-1,2-thiazinan-3-one 1,1-dioxide

A mixture of 6-nitro-1,2-thiazinan-3-one 1,1-dioxide (1 equiv.) andpalladium on activated carbon (10% wt) in THE is hydrogenated until thedisappearance of the starting material. The mixture is filtered throughCelite® and concentrated to give 6-amino-1,2-thiazinan-3-one1,1-dioxide.

4-Fluoro-2′-sulfonyl-thalidomide

A mixture of 3-fluorophthalic anhydride (1 equiv.),6-amino-1,2-thiazinan-3-one 1,1-dioxide (1 equiv.), and potassiumacetate (2.5 equiv.) in acetic acid is stirred at 120° C. overnight. Thedark mixture is cooled and filtered. The filter cake is dissolved in DCMand washed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide 4-fluoro-2′-sulfonyl-thalidomide.

2′-Sulfonyl Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.), 4-fluoro-2′-sulfonyl-thalidomide (1equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to give 2′-sulfonyl pomalidomidederivatives. (Chem Biol. 2015, 22, 755-763)

Oxetano Sulfonamide Glutarimide Derivatives

General Procedure Example 32: 6′-Oxetano-2′-Sulfonyl PomalidomideDerivatives

Sodium1-amino-3-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)propane-1-sulfonate

A solution of sodium bisulfite (1 equiv.) in water is slowly added tothe solution of2-methyl-N-(3-(3-oxopropyl)oxetan-3-yl)propane-2-sulfinamide(preparation was mentioned above) (1 equiv.) in methanol. The mixture isstirred for 60 min at RT, and then the solvent is removed to providesodium3-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)-1-hydroxypropane-1-sulfonate,which is used for the next step without further purification.

An aqueous solution of ammonia (30%, 1 equiv.) is added to a solution ofsodium3-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)-1-hydroxypropane-1-sulfonate(1 equiv.) in MeOH:H₂O 1:1, and the mixture is stirred at roomtemperature. After 1 h, the reaction is concentrated to provide sodium1-amino-3-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)propane-1-sulfonatewithout further purification. (ACS Med. Chem. Lett. 2014, 5, 1152)

1-Amino-3-(3-aminooxetan-3-yl)propane-1-sulfonic acid

Sodium1-amino-3-(3-((tert-butylsulfinyl)amino)oxetan-3-yl)propane-1-sulfonate(1 equiv.) is dissolve in 12 M HCl (excess) and stirred at rt until theconsumption of the starting material. Solvent is then removed in vacuoto provide 1-amino-3-(3-aminooxetan-3-yl)propane-1-sulfonic acid.

7-Amino-2-oxa-6-thia-5-azaspiro[3.5]nonane 6,6-dioxide

1-Amino-3-(3-aminooxetan-3-yl)propane-1-sulfonic acid (1 equiv.) isdissolved in POCl₃ (diluted) and stirred at 100° C. until theconsumption of the starting material. Solvent is removed in vacuo andthe residue is dissolved in DCM and washed carefully with saturatedsodium carbonate, then brine. The organic layer is dried (Na₂SO₄),concentrated, and purified by column chromatography on silica gel togive 7-amino-2-oxa-6-thia-5-azaspiro[3.5]nonane 6,6-dioxide.

4-Fluoro-6′-oxetano-2′-sulfonyl-thalidomide

A mixture of 3-fluorophthalic anhydride (1 equiv.),7-amino-2-oxa-6-thia-5-azaspiro[3.5]nonane 6,6-dioxide (1 equiv.), andpotassium acetate (2.5 equiv.) in acetic acid is stirred at 120° C.overnight. The dark mixture is cooled and filtered. The filter cake isdissolved in DCM and washed with saturated NaHCO₃ and brine. The organiclayer is dried (Na₂SO₄) and concentrated to provide4-fluoro-6′-oxetano-2′-sulfonyl-thalidomide.

6′-Oxetano-2′-Sulfonyl Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),4-fluoro-6′-oxetano-2′-sulfonyl-thalidomide (1 equiv.) and DIEA (2equiv.) in dry DMF is stirred at 90° C. for 12 h. The mixture is cooledto room temperature, poured into water and extracted with ethyl acetate.The combined organic phases are washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Thecrude residue is purified by column chromatography on silica gel to give6′-oxetano-2′-sulfonyl pomalidomide derivatives. (Chem Biol. 2015, 22,755-763)

General Procedure Example 33: 2′-Oxetano-6′-Sulfonyl PomalidomideDerivatives

Phenyl 3-nitropropane-1-sulfonate

A mixture of phenyl ethenesulfonate (1 equiv.) and nitromethane (1equiv.) is heated to 80° C. and, at 80° C., ethyldiisopropylamine (2equiv.) is added dropwise. The mixture is stirred at 80° C. till theconsumption of starting materials. Cooling to RT is followed by additionof a 2 M aqueous HCl solution and extraction 3 times with EtOAc. Dryingover Na₂SO₄ and removal of the solvent in vacuo are followed bycoevaporation 3 times with toluene to provide phenyl3-nitropropane-1-sulfonate. (PCT Int. Appl., 2006050830, 18 May 2006)

Phenyl 3-nitro-3-(oxetan-3-ylidene)propane-1-sulfonate

To phenyl 3-nitropropane-1-sulfonate (1.0 equiv.) is added oxetan-3-one(1.3 equiv.) and Et₃N (0.2 equiv.), and the mixture is stirred at RT for75 min. Then it is dissolved in CH₂Cl₂ and the solution is cooled to−78° C. Et₃N (3.0 equiv.) is added followed by MsCl (2.5 equiv.), andthe mixture is stirred at −78° C. for 30 min, when it is allowed to warmto −25° C. over ca. 45 min. After stirring at RT for 20 min, it isquenched with HCl (0.1 M in H₂O). The resulting mixture is diluted withCH₂Cl₂, and the phases are separated. The aqueous phase is extractedwith CH₂Cl₂, and the combined organic layers are dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification of the residue bycolumn chromatography on silica gel provides phenyl3-nitro-3-(oxetan-3-ylidene)propane-1-sulfonate. (Org. Lett. 2013, 15,4312)

Phenyl3-(3-((4-methoxybenzyl)amino)oxetan-3-yl)-3-nitropropane-1-sulfonate

To a cooled (0° C.) solution of phenyl3-nitro-3-(oxetan-3-ylidene)propane-1-sulfonate (1.0 equiv.) in THE isadded 4-methoxybenzylamine (1.0 equiv.), and the mixture is stirred at0° C. for 30 min. Then it is allowed to warm to RT and stirring iscontinued for another 10 min. At this point the mixture is concentratedin vacuo and the residue is purified by column chromatography on silicagel to provide phenyl3-(3-((4-methoxybenzyl)amino)oxetan-3-yl)-3-nitropropane-1-sulfonate.(Org. Lett. 2013, 15, 4312)

Phenyl3-(hydroxyimino)-3-(3-((4-methoxybenzyl)amino)oxetan-3-yl)propane-1-sulfonate

To a solution of phenyl3-(3-((4-methoxybenzyl)amino)oxetan-3-yl)-3-nitropropane-1-sulfonate(1.0 equiv.) in THE is added at RT tetrabutylammonium iodide (0.05equiv.), benzyl bromide (1.2 equiv.), and potassium hydroxide (1.2equiv.). The mixture is stirred at RT for 3.5 h. Then it is diluted withEt₂O and washed with saturated aqueous NaCl. Then it is dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue is purified by columnchromatography on silica gel to provide phenyl3-(hydroxyimino)-3-(3-((4-methoxybenzyl)amino)oxetan-3-yl)propane-1-sulfonateas a mixture of oxime isomers. (Org. Lett. 2013, 15, 4312)

9-(Hydroxyimino)-5-(4-methoxybenzyl)-2-oxa-6-thia-5-azaspiro[3.5]nonane6,6-dioxide

A solution of phenyl3-(hydroxyimino)-3-(3-((4-methoxybenzyl)amino)oxetan-3-yl)propane-1-sulfonate(mixture of oxime isomers; 1.0 equiv.) in xylenes is heated to 140° C.and stirred at that temperature for 23 h. Then it is cooled to RT andconcentrated in vacuo. The residue is purified by column chromatographyon silica gel to provide9-(hydroxyimino)-5-(4-methoxybenzyl)-2-oxa-6-thia-5-azaspiro[3.5]nonane6,6-dioxide. (Org. Lett. 2013, 15, 4312)

9-Amino-5-(4-methoxybenzyl)-2-oxa-6-thia-5-azaspiro[3.5]nonane6,6-dioxide

Raney-Ni (50% slurry in H₂O) is washed with EtOH (3×), then is added asolution of9-(hydroxyimino)-5-(4-methoxybenzyl)-2-oxa-6-thia-5-azaspiro[3.5]nonane6,6-dioxide (1.0 equiv.) in EtOH, and the mixture is diluted with EtOH.A hydrogen atmosphere (balloon) is built up, and the mixture isvigorously stirred at RT for 9 h. Then the atmosphere is changed to N₂and the mixture is filtered over Celite® and washed with MeOH. Thefiltrate is then concentrated in vacuo. The crude product is dissolvedin CH₂Cl₂ and filtered again over Celite®. The filtrate is concentratedin vacuo to afford9-amino-5-(4-methoxybenzyl)-2-oxa-6-thia-5-azaspiro[3.5]nonane6,6-dioxide. (Org. Lett. 2013, 15, 4312)

4-Fluoro-2′-oxetano-6′-sulfonyl-thalidomide

A mixture of 3-fluorophthalic anhydride (1 equiv.),9-amino-5-(4-methoxybenzyl)-2-oxa-6-thia-5-azaspiro[3.5]nonane6,6-dioxide (1 equiv.), and potassium acetate (2.5 equiv.) in aceticacid is stirred at 120° C. overnight. The dark mixture is cooled andfiltered. The filter cake is dissolved in DCM and washed with saturatedNaHCO₃ and brine. The organic layer is dried (Na₂SO₄) and concentratedto provide 4-fluoro-2′-oxetano-6′-sulfonyl-thalidomide.

2′-Oxetano-6′-Sulfonyl Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),4-fluoro-2′-oxetano-6′-sulfonyl-thalidomide (1 equiv.) and DIEA (2equiv.) in dry DMF is stirred at 90° C. for 12 h. The mixture is cooledto room temperature, poured into water and extracted with ethyl acetate.The combined organic phases are washed with water and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. (ChemBiol. 2015, 22, 755-763)

To a solution of the resulting residue (1.0 equiv) in CH₃CN, cooled to0° C., is added a solution of CAN (3.0 equiv) in H₂O, and the yellowclear solution is stirred at 0° C. for 2 h. Then it is diluted withEtOAc and quenched with half saturated aqueous NaCl and diluted withEtOAc and H₂O. The phases are separated, and the aqueous phase isextracted with EtOAc (2×) and CH₂C₂(2×). The combined organic phases aredried (Na₂SO₄), filtered, and concentrated in vacuo. The residue ispurified by column chromatography on silica gel to provide2′-oxetano-6′-sulfonyl pomalidomide derivatives. (Org. Lett. 2013, 15,4312)

7-Membered Imides

General Procedure Example 34: 7-Membered Pomalidomide Derivatives

4-Fluoro-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione

A mixture of 3-fluorophthalic anhydride (1 equiv.), 3-aminoazepan-2-one(1 equiv.), and potassium acetate (2.5 equiv.) in acetic acid is stirredat 120° C. overnight. The dark mixture is cooled and filtered. Thefilter cake is dissolved in DCM and washed with saturated NaHCO₃ andbrine. The organic layer is dried (Na₂SO₄) and concentrated to provide4-fluoro-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione.

2-(2,7-Dioxoazepan-3-yl)-4-fluoroisoindoline-1,3-dione

A solution of 4-fluoro-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione (1equiv.), manganic acetylacetonate (0.01 wt equiv.), and 68.8% t-butylhydroperoxide (1.5 equiv.) is stirred at rt for 4 d. The mixture isconcentrated and purified by column chromatography on silica gel toprovide 2-(2,7-dioxoazepan-3-yl)-4-fluoroisoindoline-1,3-dione. (J. Org.Chem. 1970, 35, 2121)

7-Membered Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),2-(2,7-dioxoazepan-3-yl)-4-fluoroisoindoline-1,3-dione (1 equiv.) andDIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h. The mixture iscooled to room temperature, poured into water and extracted with ethylacetate. The combined organic phases are washed with water and brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The crude residue is purified by column chromatography onsilica gel to give 7-membered pomalidomide derivatives. (Chem Biol.2015, 22, 755-763)

[3.1.0] System

General Procedure Example 35: [3.1.0] Pomalidomide Derivatives

1-(tert-Butyl) 3-ethyl 2-chloromalonate

A solution of tert-butyl ethyl malonate (1 equiv.) in dry MeCN is addedto N-chlorosuccinimide (1.2 equiv.) and magnesium perchlorate (0.3equiv.). The reaction mixture is stirred for 4 hours. After the solventis removed on a rotary evaporator, the mixture is diluted with EtOAc andwashed with brine. The organic layers are dried with Na₂SO₄, andconcentrated in vacuo. The residue is purified by column chromatographyon silica gel to afford 1-(tert-butyl) 3-ethyl 2-chloromalonate. (Org.Biomol. Chem. 2014, 12, 1510)

1-(tert-Butyl) 1,2-diethyl cyclopropane-1,1,2-tricarboxylate

To a stirred slurry of NaH (60% in mineral oil, 1 equiv.) in anhydrousEt₂O is added 1-(tert-butyl) 3-ethyl 2-chloromalonate (1 equiv.) andethyl acrylate (1 equiv.) during which the temperature is maintainedbetween 25 and 30° C. The mixture is stirred at room temperature for 24h, and then unreacted NaH is decomposed with methanol. H₂O is added, andthe organic layer is separated, dried over Na₂SO₄, filtered, andconcentrated. The residue is purified by column chromatography on silicagel to afford 1-(tert-butyl) 1,2-diethylcyclopropane-1,1,2-tricarboxylate. (J. Med. Chem. 1981, 24, 481)

1-(tert-Butoxycarbonyl)cyclopropane-1,2-dicarboxylic acid

A mixture of 1-(tert-butyl) 1,2-diethylcyclopropane-1,1,2-tricarboxylate (1 equiv.) and NaOH (2 equiv.) in 1:1EtOH-H₂O is stirred at rt for 6 h and then is evaporated to one-halfvolume. The aqueous solution is extracted with Et₂O, chilled in ice, andthen made acidic with 1 N HCl. Crystalline product is collected byfiltration and is recrystallized to give the1-(tert-butoxycarbonyl)cyclopropane-1,2-dicarboxylic acid.

3-(4-Methoxybenzyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-1-carboxylicacid

A solution of 1-(tert-butoxycarbonyl)cyclopropane-1,2-dicarboxylic acid(1 equiv.) in xylene (isomeric mixture) is boiled under a water trap for5 h and cooled. To this solution of the intermediary anhydride formedduring the reaction is added a solution of PMBNH₂ (1 equiv.) in xylene.The mixture is boiled for a further 15 h and evaporated to dryness. (J.Med. Chem. 1991, 34, 1333). The residue is dissolved in 1:1 TFA/DCM andstirred at rt for 2 h. Solvents are evaporated to provide3-(4-methoxybenzyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-1-carboxylicacid.

tert-Butyl(3-(4-methoxybenzyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexan-1-yl)carbamate

To a solution of3-(4-methoxybenzyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-1-carboxylicacid (1 equiv.) in toluene is added triethylamine (1.2 equiv.).Diphenylphosphoryl azide (1.1 equiv.) is added dropwise and the mixtureis heated to reflux while stirring for 30 min. The mixture is thencooled to rt and quenched with saturated aqueous NH₄C₁. After separationof the two phases, the aqueous solution is extracted with Et₂O (3×) andthe combined organic layers are washed with brine, dried with anhydrousNa₂SO₄ and concentrated in vacuo. The crude product is purified by flashchromatography on silica gel to afford isocyanate. (J. Org. Chem. 2005,70, 6118) To a solution of the isocyanate (1.0 equiv. of 0.2 M inbenzene) is added the t-butyl alcohol (1.5 equiv). Titaniumtetratbutoxide (0.10 equiv.) is then added, and the mixture is stirredat 120° C. until completion. After quenching with saturated aqueousNH₄Cl and separating the two phases, the aqueous layer is extractedthree times with CH₂Cl₂, and the combined organic layers are dried withanhydrous Na₂SO₄, and concentrated in vacuo. The residue is purified byflash chromatography on silica gel to afford tert-butyl(3-(4-methoxybenzyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexan-1-yl)carbamate.(J. Org. Chem. 2005, 70, 6118)

1-Amino-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

A solution of tert-butyl(3-(4-methoxybenzyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexan-1-yl)carbamate(1 equiv.) in 1:1 TFA/DCM is stirred at rt for 2 h. Solvents areevaporated to provide1-amino-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hexane-2,4-dione.

2-(2,4-Dioxo-3-azabicyclo[3.1.0]hexan-1-yl)-4-fluoroisoindoline-1,3-dione

A mixture of 3-fluorophthalic anhydride (1 equiv.),1-amino-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (1equiv.), and potassium acetate (2.5 equiv.) in acetic acid is stirred at120° C. overnight. The dark mixture is cooled and filtered. The filtercake is dissolved in DCM and washed with saturated NaHCO₃ and brine. Theorganic layer is dried (Na₂SO₄) and concentrated to provide 4-fluoroadduct.

To a solution of the resulting residue (1.0 equiv) in CH₃CN, cooled to0° C., is added a solution of CAN (3.0 equiv) in H₂O, and the yellowclear solution is stirred at 0° C. for 2 h. Then it is diluted withEtOAc and quenched with half saturated aqueous NaCl and diluted withEtOAc and H₂O. The phases are separated, and the aqueous phase isextracted with EtOAc (2×) and CH₂Cl₂ (2×). The combined organic phasesare dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue ispurified by column chromatography on silica gel to provide2-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-1-yl)-4-fluoroisoindoline-1,3-dione.(Org. Lett. 2013, 15, 4312)

[3.1.0] Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),2-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-1-yl)-4-fluoroisoindoline-1,3-dione(1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to give [3.1.0] pomalidomidederivatives. (Chem Biol. 2015, 22, 755-763)

[4.1.0] System

General Procedure Example 36: [4.1.0] Pomalidomide Derivatives

Methyl 2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate

Known compound and procedure reported in PCT Int. Appl., 2010007032, 21Jan. 2010.

tert-Butyl (2-oxo-3-azabicyclo[4.1.0]heptan-1-yl)carbamate

A mixture of methyl 2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate (1equiv.) and LiOH (2 equiv.) in 1:1 MeOH—H₂O is stirred at rt for 6 h andthen is evaporated to one-half volume. The aqueous solution is extractedwith Et₂O, chilled in ice, and then made acidic with 1 N HCl.Crystalline product is collected by filtration to give the2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylic acid.

To a solution of 2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylic acid (1equiv.) in toluene is added triethylamine (1.2 equiv.).Diphenylphosphoryl azide (1.1 equiv.) is added dropwise and the mixtureis heated to reflux while stirring for 30 min. The mixture is thencooled to rt and quenched with saturated aqueous NH₄Cl. After separationof the two phases, the aqueous solution is extracted with Et₂O (3×) andthe combined organic layers are washed with brine, dried with anhydrousNa₂SO₄ and concentrated in vacuo. The crude product is purified by flashchromatography on silica gel to afford isocyanate. (J. Org. Chem. 2005,70, 6118)

To a solution of the isocyanate (1.0 equiv. of 0.2 M in benzene) isadded the t-butyl alcohol (1.5 equiv). Titanium tetratbutoxide (0.10equiv.) is then added, and the mixture is stirred at 120° C. untilcompletion. After quenching with saturated aqueous NH₄Cl and separatingthe two phases, the aqueous layer is extracted three times with CH₂Cl₂,and the combined organic layers are dried with anhydrous Na₂SO₄, andconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel to afford tert-butyl(2-oxo-3-azabicyclo[4.1.0]heptan-1-yl)carbamate. (J. Org. Chem. 2005,70, 6118)

tert-Butyl (2,4-dioxo-3-azabicyclo[4.1.0]heptan-1-yl)carbamate

A solution of tert-butyl (2-oxo-3-azabicyclo[4.1.0]heptan-1-yl)carbamate(1 equiv.), manganic acetylacetonate (0.01 wt equiv.), and 68.8% t-butylhydroperoxide (1.5 equiv.) is stirred at rt for 4 d. The mixture isconcentrated and purified by column chromatography on silica gel toprovide tert-butyl (2,4-dioxo-3-azabicyclo[4.1.0]heptan-1-yl)carbamate.(J. Org. Chem. 1970, 35, 2121)

1-Amino-3-azabicyclo[4.1.0]heptane-2,4-dione

A solution of tert-butyl(2,4-dioxo-3-azabicyclo[4.1.0]heptan-1-yl)carbamate (1 equiv.) in 1:1TFA/DCM is stirred at rt for 2 h. Solvents are evaporated to provide1-amino-3-azabicyclo[4.1.0]heptane-2,4-dione.

2-(2,4-Dioxo-3-azabicyclo[4.1.0]heptan-1-yl)-4-fluoroisoindoline-1,3-dione

A mixture of 3-fluorophthalic anhydride (1 equiv.),1-amino-3-azabicyclo[4.1.0]heptane-2,4-dione (1 equiv.), and potassiumacetate (2.5 equiv.) in acetic acid is stirred at 120° C. overnight. Thedark mixture is cooled and filtered. The filter cake is dissolved in DCMand washed with saturated NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated to provide2-(2,4-dioxo-3-azabicyclo[4.1.0]heptan-1-yl)-4-fluoroisoindoline-1,3-dione.

[4.1.0] Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),2-(2,4-dioxo-3-azabicyclo[4.1.0]heptan-1-yl)-4-fluoroisoindoline-1,3-dione(1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude residue is purified bycolumn chromatography on silica gel to give [4.1.0] pomalidomidederivatives. (Chem Biol. 2015, 22, 755-763)

[3.1.1] System

General Procedure Example 37: [3.1.1] Pomalidomide Derivatives

N-Acryloyl-2-fluoro-N-(4-methoxybenzyl)acrylamide

A solution of 2-fluoroacryloyl chloride (1 equiv.) is cooled to 0° C.and added dropwise to a precooled solution ofN-(4-methoxybenzyl)acrylamide (1 equiv.) and triethylamine (2 equiv.) inmethylene chloride. The mixture is stirred for 1.5 h at room temperatureand evaporated to dryness. The residue is extracted with ether, thefiltrate is evaporated. The crude residue is purified by columnchromatography on silica gel to giveN-acryloyl-2-fluoro-N-(4-methoxybenzyl)acrylamide. (J. Med. Chem. 1991,34, 1333)

1-Fluoro-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

A solution of N-acryloyl-2-fluoro-N-(4-methoxybenzyl)acrylamide (1equiv.) and 2,6-di-tert-butyl-p-cresionl (13.75 equiv.) in1,2-dichlorbenzene is stirred at 170° C. for 1.5 h. After concentrationby evaporation, the residue is purified by column chromatography onsilica gel to give1-fluoro-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione.

1-Amino-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

Under nitrogen atmosphere, a mixture of1-fluoro-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione (1equiv.), sodium azide (1.2 equiv.), and Al(OTf)₃ (0.3 equiv.) in dryCH₂Cl₂ is stirred under reflux for 12 h. The mixture is poured intowater and extracted with CH₂Cl₂ (3×). The combined organic layers aredried over Na₂SO₄ and concentrated under reduced pressure. The residueis purified by column chromatography on silica gel to give1-azido-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione.

The azide obtained above is dissolved in methanol and added palladium onactivated carbon (10% wt). The mixture is hydrogenated until theconsumption of the starting material. After filtration andconcentration, the residue is purified by column chromatography onsilica gel to give1-amino-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione.

1-(4-Fluoro-1,3-dioxoisoindolin-2-yl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

A mixture of 3-fluorophthalic anhydride (1 equiv.),1-amino-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione (2.5equiv.) in acetic acid is stirred at 120° C. overnight. The dark mixtureis cooled and filtered. The filter cake is dissolved in DCM and washedwith saturated NaHCO₃ and brine. The organic layer is dried (Na₂SO₄) andconcentrated to provide1-(4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione.

[3.1.1] Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),1-(4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione(1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. (Chem Biol. 2015, 22, 755-763)

To a solution of the resulting residue (1.0 equiv) in CH₃CN, cooled to0° C., is added a solution of CAN (3.0 equiv) in H₂O, and the yellowclear solution is stirred at 0° C. for 2 h. Then it is diluted withEtOAc and quenched with half saturated aqueous NaCl and diluted withEtOAc and H₂O. The phases are separated, and the aqueous phase isextracted with EtOAc (2×) and CH₂C₂(2×). The combined organic phases aredried (Na₂SO₄), filtered, and concentrated in vacuo. The residue ispurified by column chromatography on silica gel to provide[3.1.1]pomalidomide derivatives. (Org. Lett. 2013, 15, 4312)

[3.2.1] System

General Procedure Example 38: [3.2.1] Pomalidomide Derivatives

(1R,4S)-2-Oxobicyclo[2.2.1]heptane-1-carboxylic acid

Known compound and procedure reported in J. Org. Chem. 1993, 58, 3668.

tert-Butyl ((1R,4S)-2-oxobicyclo[2.2.1]heptan-1-yl)carbamate

To a solution of (1R,4S)-2-oxobicyclo[2.2.1]heptane-1-carboxylic acid (1equiv.) in toluene is added triethylamine (1.2 equiv.).Diphenylphosphoryl azide (1.1 equiv.) is added dropwise and the mixtureis heated to reflux while stirring for 30 min. The mixture is thencooled to rt and quenched with saturated aqueous NH₄Cl. After separationof the two phases, the aqueous solution is extracted with Et₂O (3×) andthe combined organic layers are washed with brine, dried with anhydrousNa₂SO₄ and concentrated in vacuo. The crude product is purified by flashchromatography on silica gel to afford isocyanate. (J. Org. Chem. 2005,70, 6118)

To a solution of the isocyanate (1.0 equiv. of 0.2 M in benzene) isadded the t-butyl alcohol (1.5 equiv). Titanium tetratbutoxide (0.10equiv.) is then added, and the mixture is stirred at 120° C. untilcompletion. After quenching with saturated aqueous NH₄Cl and separatingthe two phases, the aqueous layer is extracted three times with CH₂Cl₂,and the combined organic layers are dried with anhydrous Na₂SO₄, andconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel to afford tert-butyl((1R,4S)-2-oxobicyclo[2.2.1]heptan-1-yl)carbamate. (J. Org. Chem. 2005,70, 6118)

tert-Butyl (2,4-dioxo-3-azabicyclo[3.2.1]octan-1-yl)carbamate

tert-Butyl ((1R,4S)-2-oxobicyclo[2.2.1]heptan-1-yl)carbamate (1 equiv.)is mixed with selenium dioxide (1.1 equiv.), dissolved in acetic acidand refluxed for 18 h. The reaction mixture is filtered, concentrated tosmaller volume and 30% hydrogen peroxide (excess) is added. Aftercooling to 0° C. the reaction is filtered, dried and crystallized fromtoluene/hexane to provide anhydride. The resulting anhydride (1 equiv.)is dissolved in 25% aqueous ammonia (excess) and evaporated to dryness.The residue is heated at 180° C. for 0.5 h, dissolved in chloroform,decolorized with silica gel, filtered and the solvent is evaporated. Theresidue is purified by flash chromatography on silica gel to affordtert-butyl (2,4-dioxo-3-azabicyclo[3.2.1]octan-1-yl)carbamate.(Tetrahedron: Asymmetry 2000, 11, 3113-3122)

1-Amino-3-azabicyclo[3.2.1]octane-2,4-dione

A solution of tert-butyl(2,4-dioxo-3-azabicyclo[3.2.1]octan-1-yl)carbamate (1 equiv.) in 1:1TFA/DCM is stirred at rt for 2 h. Solvents are evaporated to provide1-amino-3-azabicyclo[3.2.1]octane-2,4-dione.

2-(2,4-Dioxo-3-azabicyclo[3.2.1]octan-1-yl)-4-fluoroisoindoline-1,3-dione

A mixture of 3-fluorophthalic anhydride (1 equiv.),1-amino-3-azabicyclo[3.2.1]octane-2,4-dione (2.5 equiv.) in acetic acidis stirred at 120° C. overnight. The dark mixture is cooled andfiltered. The filter cake is dissolved in DCM and washed with saturatedNaHCO₃ and brine. The organic layer is dried (Na₂SO₄) and concentratedto provide2-(2,4-dioxo-3-azabicyclo[3.2.1]octan-1-yl)-4-fluoroisoindoline-1,3-dione.

[3.2.1] Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),2-(2,4-dioxo-3-azabicyclo[3.2.1]octan-1-yl)-4-fluoroisoindoline-1,3-dione(1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is purified by columnchromatography on silica gel to give [3.2.1] pomalidomide derivatives.(Chem Biol. 2015, 22, 755-763)

4′-Spiroglutarimide

General Procedure Example 39: 4′-Spiro Pomalidomide Derivatives

4-Bromo-6-azaspiro[2.5]octane-5,7-dione

Bromine (1 equiv.) is added to a solution of6-azaspiro[2.5]octane-5,7-dione (1 equiv.) in 1,1,2-trichloroethane atroom temperature. The mixture is allowed to stir for 2 hours at 110° C.and then for 1 hour at room temperature. The reaction mixture isconcentrated in vacuo and the resulting residue is purified by flashcolumn chromatography on silica gel to provide4-bromo-6-azaspiro[2.5]octane-5,7-dione. (PCT Int. Appl., 2013033901, 14Mar. 2013)

4-Amino-6-azaspiro[2.5]octane-5,7-dione

4-Bromo-6-azaspiro[2.5]octane-5,7-dione (1 equiv.) is dissolved in DMFand NaN₃ (3 equiv.) is added. The resulting mixture is heated at 50° C.for 3 h. Solvent is removed in vacuo and the crude azide is dried undervacuum. (U.S. Pat. Appl. Publ., 20040006062, 8 Jan. 2004) The crudeazide is dissolved in methanol and palladium on activated carbon (10%wt) is added. The mixture is hydrogenated at rt until the consumption ofstarting material. The mixture is filtered, and concentrated. Theresidue is purified by flash column chromatography on silica gel toprovide 4-amino-6-azaspiro[2.5]octane-5,7-dione.

2-(5,7-Dioxo-6-azaspiro[2.5]octan-4-yl)-4-fluoroisoindoline-1,3-dione

A mixture of 3-fluorophthalic anhydride (1 equiv.),4-amino-6-azaspiro[2.5]octane-5,7-dione (2.5 equiv.) in acetic acid isstirred at 120° C. overnight. The dark mixture is cooled and filtered.The filter cake is dissolved in DCM and washed with saturated NaHCO₃ andbrine. The organic layer is dried (Na₂SO₄) and concentrated to provide2-(5,7-dioxo-6-azaspiro[2.5]octan-4-yl)-4-fluoroisoindoline-1,3-dione.

4′-Spiro Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),2-(5,7-dioxo-6-azaspiro[2.5]octan-4-yl)-4-fluoroisoindoline-1,3-dione (1equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is purified by columnchromatography on silica gel to give 4′-spiro pomalidomide derivatives.(Chem Biol. 2015, 22, 755-763)

5′-Spiroglutarimide

General Procedure Example 40: 5′-Spiro Pomalidomide Derivatives

di-tert-Butyl 4-methylene-5-oxopyrrolidine-1,2-dicarboxylate

Known compound and procedure reported in Tetrahedron Lett. 2004, 45,3241.

Methyl1-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)cyclopropane-1-carboxylate

Known compound and procedures reported in J. Chem. Soc., Perkin Trans.1, 1997, 3519.

2-Amino-3-(1-carbamoylcyclopropyl)propanoic acid

To a stirred solution of methyl1-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)cyclopropane-1-carboxylate(1 equiv.) in methanol at 0° C. in a 2-5 mL microwave vial is addedmagnesium nitride (5 equiv.) in a single portion. The vial is sealedimmediately and allowed to warm to room temperature in a water bath.After approximately 1 hour the reaction is heated at 80° C. for 24 h.The reaction is allowed to cool to room temperature and diluted withchloroform and water. The aqueous layer is neutralized with 3 N HCl andthe organic layer is separated. The aqueous layer is further extractedwith chloroform (2×) and the organic layers are combined, passed througha hydrophobic frit and concentrated in vacuo to afford crudecarboxamide. (Org. Lett. 2008, 10, 3623)

The resulting carboxamide (1 equiv.) is dissolved in 1:1 TFA/DCM andstirred at rt for 2 h. Solvents are evaporated and the residue ispurified by column chromatography on silica gel to provide2-amino-3-(1-carbamoylcyclopropyl)propanoic acid.

7-Amino-5-azaspiro[2.5]octane-4,6-dione

A mixture of 2-amino-3-(1-carbamoylcyclopropyl)propanoic acid (1equiv.), alumina (3 wt. equiv.) in toluene is heated under reflux for1.5 h. The water produced during the reaction is collected in aDean-Stark trap. The reaction mixture is allowed to cool and the aluminais filtered off and washed with 10% MeOH/CH₂Cl₂. The filtration iscombined and the solvent is removed under vacuum to provide7-amino-5-azaspiro[2.5]octane-4,6-dione. (Org. Biomol. Chem. 2015, 13,7624-7627)

2-(4,6-Dioxo-5-azaspiro[2.5]octan-7-yl)-4-fluoroisoindoline-1,3-dione

A mixture of 3-fluorophthalic anhydride (1 equiv.),7-amino-5-azaspiro[2.5]octane-4,6-dione (2.5 equiv.) in acetic acid isstirred at 120° C. overnight. The dark mixture is cooled and filtered.The filter cake is dissolved in DCM and washed with saturated NaHCO₃ andbrine. The organic layer is dried (Na₂SO₄) and concentrated to provide2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)-4-fluoroisoindoline-1,3-dione.

5′-Spiro Pomalidomide Derivatives

A mixture of alkyl amine (1 equiv.),2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)-4-fluoroisoindoline-1,3-dione (1equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90° C. for 12 h.The mixture is cooled to room temperature, poured into water andextracted with ethyl acetate. The combined organic phases are washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is purified by columnchromatography on silica gel to give 5′-spiro pomalidomide derivatives.(Chem Biol. 2015, 22, 755-763)

Intermediate Functionalization in Preparation for Linker Installation

General procedure to convert 4-fluoro-thalidomide to4-bromo-thalidomide, which then be used to convert to various functionalgroups for linker installation.

General procedure to convert lenalidomide to 4-bromo-lenalidomide, whichthen be used to convert to various functional groups for linkerinstallation.

General Procedure Example 41: N-Boc 5′-Spiro-Pomalidomide

N-Boc 4-Fluoro-5′-spiro-thalidomide

To a stirred solution of 4-fluoro-5′-spiro-thalidomide (1.0 equiv.) inDMF is added potassium carbonate (2.0 equiv.). The resulting solution iscooled to 0-5° C. and Boc anhydride (3.0 equiv.) is added slowly as asolution in 1,4-dioxane (also cooled). The resulting mixture is stirredat 0° C. for 1 h and allowed to warm to room temperature overnight.Water is then added and the aqueous layer is extracted 2 times with DCMand concentrated. The residue is purified by column chromatography onsilica gel to obtain N-Boc 4-fluoro-5′-spiro-thalidomide. (WO2014/147531 A2)

N-Boc 4-Benzylamino-5′-spiro-thalidomide

A mixture containing N-Boc 4-fluoro-5′-spiro-thalidomide (1 equiv.) andbenzylamine (2 equiv.) in CH₃CN is stirred at room temperature until theconsumption of the starting material. After concentration of thereaction mixture under reduced pressure, the residue is diluted withwater and extracted with CHCl₃. The organic layer is dried andconcentrated to dryness under reduced pressure. The residue is purifiedby flash column chromatography on silica gel to provide N-Boc4-benzylamino-5′-spiro-thalidomide. (J. Med. Chem. 1990, 33, 1645)

N-Boc 4-Amino-5-spiro-thalidomide

A mixture containing N-Boc 4-benzylamino-5′-spiro-thalidomide (1 equiv.)and 5% Pd/C (0.1 wt equiv.) in dioxane is hydrogenated at 50-55° C.until the required volume of H₂ has been taken up. The reaction mixtureis filtered to remove the catalyst. The filtrate is concentrated underreduced pressure to provide N-Boc 4-amino-5′-spiro-thalidomide. (J. Med.Chem. 1990, 33, 1645)

General Procedure Example 42: N-Boc 4-Bromo-5′-spiro-thalidomide

To a suspension of N-Boc 4-amino-5′-spiro-thalidomide (1 equiv.) in 20%HBr is added NaNO₂ (1.2 equiv.) under ice cooling. After stirring for 5min, the reaction mixture is added to a solution of CuBr (1.5 equiv.) in20% HBr. The reaction mixture is stirred at room temperature for 1 h.After neutralization with 20% NaOH, the solution is extracted withCHCl₃. The organic layer is dried and concentrated to dryness. Theresidue is purified by flash column chromatography on silica gel toprovide N-Boc 4-bromo-5′-spiro-thalidomide. (J. Med. Chem. 1990, 33,1645)

General Procedure Example 43: N-Boc 4-Hydroxyl-5′-spiro-thalidomide

15 N Sulfuric acid is cooled to 0° C., N-Boc4-bromo-5′-spiro-thalidomide (1 equiv.) is added gradually with goodstirring. After one hour, a solution of sodium nitrite (1 equiv.) inwater is added slowly while maintaining the temperature below 5° C.After another 30 minutes, the mixture is warmed to 80° C. and maintainedat this temperature until nitrogen evolution ceases. The now dark orangesolution is diluted with water and extracted with ether. The organiclayer is dried with sodium sulfate, filtered and shaken for two hourswith finely powdered barium chloride to remove traces of sulfuric acid.The solution is filtered and concentrated. The residue is purified byflash column chromatography on silica gel to provide N-Boc4-hydroxyl-5′-spiro-thalidomide. (J. Am. Chem. Soc., 1955, 77 (19), pp5092-5095)

General Procedure Example 44: N-Boc 4-Ethynyl-5′-spiro-thalidomide

A reaction vessel is charged with bis(triphenylphosphine)palladium(II)chloride (2 mol %), copper(I) iodide (4 mol %) and N-Boc4-bromo-5′-spiro-thalidomide (1 equiv.). The reaction atmosphere iscycled between nitrogen and vacuum 3 times then triethylamine (1.55equiv.) and trimethylsilylacetylene (1.25 equiv.) are added and thereaction is mixed for 24 hours. When the starting materials areconsumed, the reaction is diluted with ethyl acetate and filteredthrough a plug of Celite®. The filtrate is concentrated and the residueis purified by silica gel chromatography to provide N-Boc4-trimethylsilylethynyl-5′-spiro-thalidomide. (Org. Lett. 2014, 16,6302)

A reaction vessel is charged with N-Boc4-trimethylsilylethynyl-5′-spiro-thalidomide (1 equiv.), potassiumcarbonate (4 equiv.) and MeOH. The reaction is mixed at ambienttemperature for 8 hours then concentrated. The residue is diluted withwater and ethyl acetate. The aqueous layer is extracted with ethylacetate and the combined organic layer is dried over sodium sulfate,filtered and concentrated. The crude residue is purified by silica gelchromatography to provide N-Boc 4-ethynyl-5′-spiro-thalidomide.

General Procedure Example 45: N-Boc 4-Propargyloxy-5′-spiro-thalidomide

A reaction vessel is charged with N-Boc 4-hydroxyl-5′-spiro-thalidomide(1 equiv.) and acetone (0.25 M). To this solution is added sequentiallypotassium carbonate (4 equiv.) and propargyl bromide (1.2 equiv.). Thereaction is refluxed overnight, cooled to ambient temperature, filteredthrough a medium frit, and concentrated. The crude residue is purifiedby silica gel chromatography to provide N-Boc4-propargyloxy-5′-spiro-thalidomide. (J. Med. Chem. 2013, 56, 2828)

General Procedure Example 46: N-Boc 4-Carboxy-5′-spiro-thalidomide

A flame-dried reaction vessel is charged with N-Boc4-bromo-5′-spiro-thalidomide (1 equiv.) and the atmosphere is cycledbetween nitrogen and vacuum three times. Ether is added and the solutionis cooled to −78° C. tert-Butyllithium (2 equiv.) is added dropwise andthe reaction is mixed for 15 min then carbon dioxide gas is bubbledthrough the solution for 15 min. The reaction is warmed to ambienttemperature allowing excess carbon dioxide gas to slowly evolve fromsolution. The reaction is quenched with 1 M aq. NaOH solution and washedwith ether (2×). The pH of the aqueous layer is adjusted to 3 andextracted with ethyl acetate (3×). The combined organic layer is driedover sodium sulfate and concentrated to dryness with toluene (3×) toprovide N-Boc 4-carboxy-5′-spiro-thalidomide.

General Procedure Example 47: N-Boc 4-Hydroxymethyl-5′-spiro-thalidomide

A reaction vessel is charged with N-Boc 4-carboxy-5′-spiro-thalidomide(1 equiv.), THE and cool to 0° C. Triethylamine (1.1 equiv.) andisobutylchloroformate (1.1 equiv.) are added and the reaction mixedambient temperature for 1 hour. The reaction is filtered through amedium frit and cooled to 0° C. To the solution of mixed anhydride isadded a solution of sodium borohydride (2 equiv.) in MeOH. Upon completereduction to the corresponding benzylic alcohol, the reaction isconcentrated then treated with ethyl acetate and 10% aq. HCl. The phasesare separated and aqueous solution is extracted with ethyl acetate (3×).The combined organic layer is washed with 5% sodium bicarbonatesolution, dried over sodium sulfate, and concentrated. The residue ispurified by silica gel chromatography to provide N-Boc4-hydroxymethyl-5′-spiro-thalidomide.

General Procedure Example 48: N-Boc 4-Formyl-5′-spiro-thalidomide

A reaction vessel is charged with N-Boc4-hydroxymethyl-5′-spiro-thalidomide (1 equiv.) and manganese dioxide(10 equiv.) and DCM. The reaction is heated at reflux overnight thencooled to ambient temperature and filtered. The filtrate is concentratedand purified by silica gel chromatography to provide N-Boc4-formyl-5′-spiro-thalidomide.

General Procedure Example 49: N-Boc 4-Bromomethyl-5′-spiro-thalidomide

A reaction vessel is charged with N-Boc4-hydroxymethyl-5′-spiro-thalidomide (1 equiv.) and DCM. The solution iscooled to 0° C. and N-bromosuccinimide (1.25 equiv.) andtriphenylphosphine (1.25 equiv.) are then added. The reaction is mixedfor 3 hours then concentrated. The crude residue is purified by silicagel chromatography to provide N-Boc 4-bromomethyl-5′-spiro-thalidomide.(J. Med. Chem. 2015, 58, 1215)

General Procedure Example 50: N-Boc 4-Azidomethyl-5′-spiro-thalidomide

Sodium azide (3 equiv.) is added to a solution of N-Boc4-bromomethyl-5′-spiro-thalidomide (1 equiv.) in water and acetone (1:3,0.25 M). The reaction is heated at 60° C. for 6 hours. The reaction iscooled to ambient temperature and the solvent removed by rotaryevaporation. The aqueous layer is extracted with DCM (3×) and thecombined organic layer is dried over sodium sulfate and filtered. Thefiltrate is concentrated and the crude residue is purified by silica gelchromatography to provide N-Boc 4-azidomethyl-5′-spiro-thalidomide.(Angew. Chem. Int. Ed. 2014, 53, 10155)

Linker Installation Linker Installation Example 1: tert-Butyl7-(4-((8-hydroxyoctyl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate

A reaction vessel is charged with N-Boc 4-hydroxyl-5′-spiro-thalidomide(1 equiv.) and DMF (0.3 M) then cooled to 0° C. Sodium hydride (60%dispersion in mineral oil, 1.1 equiv.) is added and the reaction iswarmed to ambient temperature and mixed for 1 hour. The reaction iscooled to 0° C. then 8-bromooctan-1-ol (1.1 equiv.) is added and thereaction is mixed at ambient temperature overnight. DMF is removed byrotary evaporation and the residue is deposited onto silica gel andpurified by silica gel chromatography to provide tert-butyl7-(4-((8-hydroxyoctyl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate.

Linker Installation Example 2: tert-Butyl7-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate

A reaction vessel is charged with N-Boc 4-hydroxyl-5′-spiro-thalidomide(1 equiv.) and DMF (0.3 M) then cooled to 0° C. Sodium hydride (60%dispersion in mineral oil, 1.1 equiv.) is added and the reaction iswarmed to ambient temperature and mixed for 1 hour. The reaction iscooled to 0° C. then 2-(2-(2-bromoethoxy)ethoxy)ethan-1-ol (1.1 equiv.)is added and the reaction is mixed at ambient temperature overnight. DMFis removed by rotary evaporation and the residue is deposited ontosilica gel and purified by silica gel chromatography to providetert-butyl7-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate.

Linker Installation Example 3: tert-Butyl7-(4-((1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate

A reaction vessel is charged with the polymer supported catalyst(Amberlyst A-21, 1.23 mmol/g; CuI, 13 mol %). The azide (0.5 M in DCM, 1equiv.) is added dropwise followed by a solution of N-Boc4-propargyloxy-5′-spiro-thalidomide (0.5 M in DCM, 1 equiv.). Thesuspension is mixed for 12 hours at ambient temperature. The reactionsolution is filtered through a frit and the polymer cake is washed iswashed with DCM (2×). The combined filtrate is concentrated and theresidue purified by silica gel chromatography to provide tert-butyl7-(4-((1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate.(Org. Lett. 2006, 8, 1689)

Linker Installation Example 4: tert-Butyl7-(4-(2-((3,5-dihydroxy-3-methylpentyl)oxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate

tert-Butyl7-(4-(2-hydroxyethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate

A reaction vessel is charged with N-Boc 4-hydroxyl-5′-spiro-thalidomide(1 equiv.), potassium carbonate (2 equiv.) and DMF (0.5 M).2-(2-Chloroethoxy)tetrahydro-2H-pyran (1.1 equiv.) is added and thereaction is heated at 110° C. for 12 hours. The reaction is then cooledto ambient temperature and concentrated. The residue is taken up inwater and ethyl acetate and the layers separated. The aqueous layer isextracted with ethyl acetate (2×). The combined organic layer is washedwith brine, dried over sodium sulfate, filtered and concentrated. Thecrude residue is used directly in the following reaction.

A reaction vessel is charged with crude residue (1 equiv.), MeOH and DCM(1:1, 0.2 M). p-Toluenesulfonic acid (0.1 equiv.) is added and thereaction mixed at ambient temperature. Upon completion of the hydrolysisreaction, the volatiles are removed by rotary evaporation and theresidue purified by silica gel chromatography to provide tert-butyl7-(4-(2-hydroxyethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate.

tert-Butyl7-(1,3-dioxo-4-(2-(2-oxopropoxy)ethoxy)isoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate

A reaction vessel is charged with tert-butyl7-(4-(2-hydroxyethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate(1 equiv.), potassium carbonate (1.2 equiv.) and acetone (0.1 M).Chloroacetone (1.2 equiv.) is then added and the reaction heated atreflux overnight. The reaction is cooled then concentrated and the cruderesidue partitioned between water and ethyl acetate. The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×).The combined organic layers are dried over sodium sulfate, filtered andconcentrated.

The crude residue is purified by column chromatography to providetert-butyl7-(1,3-dioxo-4-(2-(2-oxopropoxy)ethoxy)isoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate.(J. Med. Chem. 2007, 50(18), 4304)

tert-Butyl7-(4-(2-((3,5-dihydroxy-3-methylpentyl)oxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate

A reaction vessel is charged with tert-butyl7-(1,3-dioxo-4-(2-(2-oxopropoxy)ethoxy)isoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate(1 equiv.), and THE (0.2 M), purged with nitrogen and cooled to −78° C.Vinylmagnesium bromide (4 equiv.) is added dropwise and the reaction iswarmed to 0° C. over 1 hour. The reaction is quenched with aq. 1% HClsolution and extracted with ethyl acetate (3×). The combined organiclayer is washed with brine, dried over sodium sulfate, filtered andconcentrated. The crude residue is purified by silica gel chromatographyto provide tert-butyl7-(4-(2-((2-hydroxy-2-methylbut-3-en-1-yl)oxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate.

Cyclohexene (4.2 equiv.) is added to a solution of BH₃.THF (1 M in THF,2 equiv.) at 0° C. under argon. After stirring for 1 hour at 0° C., asolution of tert-butyl7-(4-(2-((2-hydroxy-2-methylbut-3-en-1-yl)oxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate(1 equiv.) in THE (0.15 M) is added to the mixture at 0° C. Afterstirring for 2 hours at 0° C., 3 N NaOH (6 equiv.) and 30% H₂O₂(33%volume of aq. NaOH solution addition) is added to the mixture. Thissolution is allowed to mix at ambient temperature for 30 min. Thereaction is quenched with saturated aqueous NH₄Cl (8 volumes) at 0° C.,and the resulting mixture is extracted with ethyl acetate (3×). Thecombined extracts are washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue ispurified by silica gel chromatography to provide tert-butyl7-(4-(2-((3,5-dihydroxy-3-methylpentyl)oxy)ethoxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate.(Org. Lett. 2012, 14, 6374)

Linker Installation Example 5: tert-Butyl7-(4-((6-chloro-4-hydroxy-4-methylhex-2-yn-1-yl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate

A reaction vessel is charged with N-Boc4-propargyloxy-5′-spiro-thalidomide (1 equiv.) and the atmosphere cycledbetween nitrogen and vacuum three times. Anhydrous THE (0.1 M) is addedand the reaction cooled to −78° C. Butyllithium (1.05 equiv.) is addedand the reaction is mixed for 15 min. 5-Chloro-2-pentanone (1.1 equiv.)in THE (5 volumes) is then added and the reaction is warmed to ambienttemperature and quenched with sat. aq. ammonium chloride solution. Ethylacetate is added and the phases are separated. The aqueous layer isextracted with ethyl acetate (2×). The combined organic layers arewashed with brine, dried over sodium sulfate, filtered and concentrated.The crude residue is purified by silica gel chromatography to providetert-butyl7-(4-((6-chloro-4-hydroxy-4-methylhex-2-yn-1-yl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate.

Final Compounds Glucocorticoid Receptor Targeting Ligand(8S,9R,10S,11S,13S,14S,16R,17R)-N-(8-((2-(4,6-Dioxo-5-azaspiro[2.5]octan-7-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)-9-fluoro-11,17-dihydroxy-10,16-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxamide

tert-Butyl7-(4-((8-aminooctyl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate(1 equiv.) is dissolved in DMF and added to a solution of Dex-acid (1equiv.), DIPEA (3 equiv.). HATU (2 equiv.) is then added and the mixtureis stirred for 24 hours. The mixture is then diluted with ethyl acetateand washed with saturated sodium bicarbonate solution, water, and thenbrine. The organic layer is dried over sodium sulfate and concentrated.The crude material is then dissolved in dioxane. HCl (4N in dioxane) isadded and the solution stirred at room temperature for 12 hours. Thesolvent is then evaporated under reduced pressure and the crude productis purified by flash column chromatography on silica gel to provide(8S,9R,10S,11S,13S,14S,16R,17R)-N-(8-((2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)-9-fluoro-11,17-dihydroxy-10,16-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxamide.

FKBP Targeting Ligand2-(3-((3S)-5-(3,4-Dimethoxyphenyl)-1-(1-(3,3-dimethyl-2-oxopentanoyl)piperidin-2-yl)-1-oxopentan-3-yl)phenoxy)-N-(8-((2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)acetamide

tert-Butyl7-(4-((8-aminooctyl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate(1 equiv.) is dissolved in DMF and added to a solution of AP1479 (1equiv.), DIPEA (3 equiv.). HATU (1 equiv.) is then added and the mixtureis stirred for 24 hours. The mixture is then diluted with ethyl acetateand washed with saturated sodium bicarbonate solution, water, and thenbrine. The organic layer is dried over sodium sulfate and concentrated.The crude material is then dissolved in dioxane. HCl (4N in dioxane) isadded and the solution stirred at room temperature for 12 hours. Thesolvent is then evaporated under reduced pressure and the crude productis purified by flash column chromatography on silica gel to provide2-(3-((3S)-5-(3,4-dimethoxyphenyl)-1-(1-(3,3-dimethyl-2-oxopentanoyl)piperidin-2-yl)-1-oxopentan-3-yl)phenoxy)-N-(8-((2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)acetamide.

BRD Targeting Ligand2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-((2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)acetamide

tert-Butyl7-(4-((8-aminooctyl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate(1 equiv.) is dissolved in DMF and added to a solution of JQ-1 (1equiv.), DIPEA (3 equiv.). HATU (1 equiv.) is then added and the mixtureis stirred for 24 hours. The mixture is then diluted with ethyl acetateand washed with saturated sodium bicarbonate solution, water, and thenbrine. The organic layer is dried over sodium sulfate and concentrated.The crude material is then dissolved in dioxane. HCl (4N in dioxane) isadded and the solution stirred at room temperature for 12 hours. Thesolvent is then evaporated under reduced pressure and the crude productis purified by flash column chromatography on silica gel to provide2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-((2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)-1,3-dioxoisoindolin-4-yl)oxy)octyl)acetamide.

ABL Targeting Ligand4-((4-(7-((2-(4,6-Dioxo-5-azaspiro[2.5]octan-7-yl)-1,3-dioxoisoindolin-4-yl)oxy)-4-hydroxy-4-methylhept-5-yn-1-yl)piperazin-1-yl)methyl)-N-(3-methyl-4-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide

To a solution of tert-butyl7-(4-((7-chloro-4-hydroxy-4-methylhept-2-yn-1-yl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate(1 equiv.) in acetone is added NaI (5 equiv.). The reaction mixture isstirred at reflux temperature for 24 h, then the solvent is removedunder vacuum and crude product is dissolved in EtOAc and an aqueoussolution of Na₂SO₃ (10%). Organic layer is separated, washed with water,dried (Na₂SO₄) and evaporated under vacuum. Crude iodo product is usedin the next step without any further purification. To a solution ofN-(3-methyl-4-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-ylmethyl)benzamide(1 equiv.) and DIEA (2.5 equiv.) in DMF is added crude iodo intermediate(1 equiv.) and the resulting solution is stirred at rt for 16 h. Thesolvent is evaporated and the residue is dissolved in dioxane. HCl (4Nin dioxane) is added and the solution stirred at room temperature for 12hours. The solvent is then evaporated under reduced pressure and thecrude product is purified by flash column chromatography on silica gelto provide4-((4-(7-((2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)-1,3-dioxoisoindolin-4-yl)oxy)-4-hydroxy-4-methylhept-5-yn-1-yl)piperazin-1-yl)methyl)-N-(3-methyl-4-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide.

JAK2 Targeting Ligand4-((7-(4-(4-(8-(3,5-Difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-hydroxy-4-methylhept-2-yn-1-yl)oxy)-2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)isoindoline-1,3-dione

To a solution of tert-butyl7-(4-((7-chloro-4-hydroxy-4-methylhept-2-yn-1-yl)oxy)-1,3-dioxoisoindolin-2-yl)-4,6-dioxo-5-azaspiro[2.5]octane-5-carboxylate(1 equiv.) in acetone is added NaI (5 equiv.). The reaction mixture isstirred at reflux temperature for 24 h, then the solvent is removedunder vacuum and crude product is dissolved in EtOAc and an aqueoussolution of Na₂SO₃ (10%). Organic layer is separated, washed with water,dried (Na₂SO₄) and evaporated under vacuum. Crude iodo product is usedin the next step without any further purification. To a solution of4-(2,6-difluoro-4-(3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-5-yl)benzyl)morpholine(1 equiv.) and DIEA (2.5 equiv.) in DMF is added crude iodo intermediate(1 equiv.) and the resulting solution is stirred at rt for 16 h. Thesolvent is evaporated and the residue is dissolved in dioxane. HCl (4Nin dioxane) is added and the solution stirred at room temperature for 12hours. The solvent is then evaporated under reduced pressure and thecrude product is purified by flash column chromatography on silica gelto provide4-((7-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-hydroxy-4-methylhept-2-yn-1-yl)oxy)-2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)isoindoline-1,3-dione.

Additional Examples of Final Compounds

Preparation of Representative Targeting Ligands

(S)-6-(4-Chlorophenyl)-1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

tert-Butyl(R)-(1-((4-bromo-2-(4-chlorobenzoyl)phenyl)amino)-1-oxopropan-2-yl)carbamate

(2-Amino-5-bromophenyl)(4-chlorophenyl)methanone (1.0 equiv.) andBoc-(L)-Ala (1.0 equiv.) is suspended in DMF and cooled to 0° C. DIEA(2.0 equiv.) is added followed by HATU (1.1 equiv.) and the reaction isstirred at reduced temperature for 30 minutes and then warmed to roomtemperature. When the reaction is judged to be complete it is quenchedwith aq. ammonium chloride and extracted with ethyl acetate. Thecombined organic layers are dried over sodium sulfate, concentrated andpurified by silica gel chromatography to provide tert-butyl(R)-(1-((4-bromo-2-(4-chlorobenzoyl)phenyl)amino)-1-oxopropan-2-yl)carbamate.

(S)-7-Bromo-5-(4-chlorophenyl)-3-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one

To a stirred solution of boc protected amine in CHCl₃ at r.t., is addedhydrogen chloride gas slowly. After 20 minutes the addition is stoppedand the reaction is stirred at r.t. until deprotection is complete. Thereaction mixture is then washed with saturated bicarbonate solution (2×)and water (2×). The organic layer is concentrated under reducedpressure. The residue is dissolved in 2:1 methanol:water and the pH isadjusted to 8.5 by the addition of 1N aqueous NaOH. The reaction is thenstirred at r.t. until the cyclization is complete. MeOH is then removedunder reduced pressure and the solution is extracted with DCM (3×). Thecombined organic layer is dried over sodium sulfate, concentrated andpurified by silica gel chromatography to provide(S)-7-bromo-5-(4-chlorophenyl)-3-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one(US 2010 0261711.).

(S)-8-Bromo-6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

A solution of diazapine (1.0 equiv.) in THE is cooled to −10° C. and NaH(0.85 equiv.) is added in one portion. After an hour at reducedtemperature di-4-morphilinylphosphinic chloride (1.07 equiv.) is addedat −10° C. and the reaction is allowed to warm to r.t. and stir for 2hours. To this mixture is added a solution of acetic hydrazide (1.4equiv.) in n-butanol and stirring is continued for 30 minutes. Thesolvent is then removed under reduced pressure and the residue dissolvedin fresh dry n-butanol before refluxing for the desired time frame. Uponthe completion of the reaction the volatiles are removed by rotaryevaporation and the residue is partitioned between DCM and brine. Theorganic layer is dried, concentrated and purified by silica gelchromatography to provide(S)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine(US 2010 0261711.).

(S)-6-(4-Chlorophenyl)-1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

To a vial containing(S)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine(1 equiv.) is added Pd(PPh3)4 (20 mol %),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5equiv.), and potassium carbonate (2.5 equiv.). The vial is thenevacuated and purged under N2. To the vial is added dioxane:water (2:1).The contents were once again evacuated and purged under N2 and thereaction mixture was heated to 80° C. until the SM is converted. Themixture is then cooled to room temperature and filtered over a pad ofCelite®. The filter pad is rinsed with EtOAc (3×) and the filtrate isconcentrate. The crude material is purified by flash chromatography (WO2015156601).

(S)-4-(1,4-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenol

Methyl (R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoate

Methyl 2-amino-5-bromobenzoate (1.0 equiv.) and Boc-(L)-Ala (1.0 equiv.)is suspended in DMF and cooled to 0° C. DIEA (2.0 equiv.) is addedfollowed by HATU (1.1 equiv.) and the reaction is stirred at reducedtemperature for 30 minutes and then warmed to room temperature. When thereaction is judged to be complete it is quenched with aq. ammoniumchloride and extracted with ethyl acetate. The combined organic layersare dried over sodium sulfate, concentrated and purified by silica gelchromatography to provide methyl(R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoate.

Methyl5-bromo-2-(3-((R)-1-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-4H-1,2,4-triazol-4-yl)benzoate

Methyl (R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoateA solution of methyl(R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoate (1.0equiv.) in THE is cooled to −10° C. and NaH (0.85 equiv.) is added inone portion. After an hour at reduced temperaturedi-4-morphilinylphosphinic chloride (1.07 equiv.) is added at −10° C.and the reaction is allowed to warm to r.t. and stir for 2 hours. Tothis mixture is added a solution of acetic hydrazide (1.4 equiv.) inn-butanol and stirring is continued for 30 minutes. The solvent is thenremoved under reduced pressure and the residue dissolved in fresh dryn-butanol before refluxing for the desired time frame. Upon thecompletion of the reaction the volatiles are removed by rotaryevaporation and the residue is partitioned between DCM and brine. Theorganic layer is dried, concentrated and purified by silica gelchromatography to provide methyl(R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoate (BMCL2015, 25, 1842-48).

(S)-8-Bromo-1,4-dimethyl-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-one

Methyl (R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoateis brought up in DCM and cooled to 0° C. 4M HCl in dioxane is added andthe reaction is warmed to r.t.. When deprotection is complete thereaction is concentrated and then azeotroped from toluene (2×). Thecrude amine salt is then dissolved in THF and cooled to −40° C. at whichtime iPrMgBr solution is added dropwise (2.0 equiv.) and the reaction isstirred at reduced temp until complete conversion (BMCL 2015, 25,1842-48).

(S)-1,4-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-one

To a vial containing(S)-8-bromo-1,4-dimethyl-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-one(1 equiv.) is added Pd2 (dba) 3 (10 mol %), tri-tert-butylphosphoniumtetrafluoroborate (20 mol %),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.5 equiv.), and potassium phosphate tribasic, monohydrate (2.5equiv.). The vial is then evacuated and purged under N2. To the vial isadded 20:1 ratio by volume of dioxane:water. The contents were onceagain evacuated and purged under N2 (g) and the reaction mixture washeated to 100° C. until the SM is converted. The mixture is then cooledto room temperature and filtered over a pad of Celite®. The filter padis rinsed with EtOAc (3×) and the filtrate is concentrate. The crudematerial is purified by flash chromatography.

(S)-6-Chloro-1,4-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

(S)-1,4-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-one(1.0 equiv.) is dissolved in DCM and PCI5 (1.7 equiv.) is added inone-portion. After conversion of SM 2M sodium carbonate is added. Thebiphasic mixture is subsequently extracted with EtOAc (4×). The combinedorganic layers were dried over sodium sulfate and concentrated todryness. The resultant residue is purified by flash chromatography.

(S)-4-(1,4-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenol

To a vial containing((S)-6-chloro-1,4-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine(1 equiv.) is added Pd(PPh₃)₄(20 mol %), 4-hydroxy-Phenyl boronic acid(1.5 equiv.), and sodium carbonate (2.5 equiv.). The vial is thenevacuated and purged under N2. To the vial is added tol:DME:water(1:1:5). The contents were once again evacuated and purged under N2 andthe reaction mixture was heated to 80° C. until the SM is converted. Themixture is then cooled to room temperature and filtered over a pad ofCelite®. The filter pad is rinsed with EtOAc (3×) and the filtrate isconcentrate. The crude material is purified by flash chromatography.

Synthesis of Selected Glutarimides

Example 1: Illustrative Preparation of 5-Member Glutarimide

Step-1

To a stirred solution of 1-2 (448 mg, 3.37 mmol) and 1-1 (1000 mg, 3.37mmol) and Potassium carbonate (931 mg, 6.74 mmol) in Acetone (20.0 mL).It was stirred at room temperature for 16 hours. It was diluted withwater and extracted with ethyl acetate. Organic part was dried oversodium sulfate, concentrated under reduced pressure and purified bycolumn chromatography using (silica, gradient, 0%-30% ethyl acetate inhexane to afford 3 as off white solid. Yield-20%; LC MS: ES+349.3.

Step-2

Compound 1-3 (100 mg, 287 μmol) was taken in Ethanol (10 mL) in aparr-shaker vessel. It was degassed with argon for 10 minutes. Platinumdioxide (6.51 mg, 28.7 μmol) was added to the reaction mixture. It wasshacked in the presence of hydrogen at 50 psi for 16 h. It was filteredthrough celite and concentrated under reduced pressure and was purifiedby column chromatography using (silica, gradient, 0%-25% Ethyl acetatein hexane) to provide 1-4 as white solid. Yield-40%; LC MS: ES+351.1.

Step-3

To a stirred solution of 1-4 (32 mg, 91.3 μmol) in Acetonitrile (0.5 mL)and Water (2 mL). Ceric ammonium nitrate (99.7 mg, 182 μmol) was addedto the reaction mixture and was stirred at room temperature for 2 hours.It was diluted with water and was extracted with ethyl acetate, driedover sodium sulfate and concentrated under reduced pressure. It waspurified by preparative TLC (40% ethyl acetate in hexane) to provideCompound 1 as off white solid. Yield-19%; 1H NMR (400 MHz, DMSO-d6) δ11.51 (s, 1H), 7.71 (d, J=7.36 Hz, 1H), 7.64-7.61 (m, 2H), 7.52 (d,J=7.52 Hz, 1H), 5.23 (t, J=7.42 Hz, 1H), 4.62 (d, J=17.24 Hz, 1H), 4.37(d, J=17.24 Hz, 1H), 2.97-2.92 (m, 1H); LC MS: ES+231.3.

Example 2: Illustrative Preparation of 7-Member Glutarimide

Step-1

To a mixture of 2-1 (150 mg, 780 μmol) and 2-2 (100 mg, 780 μmol) inAcetic acid (3 mL) taken was added Ammonium acetate (60.1 mg, 780 μmol)and refluxed for 2 hours. Water was then added to the reaction mixtureand the compound was extracted with DCM. The organic phase wasseparated, dried over anhydrous sodium sulfate and evaporated in vacuoto obtain the crude which was purified by silica gel column to afford2-3 as white solid. Yield-21%; LC MS: ES+304.1.

Step-2

A mixture of periodic acid (224 mg, 984 μmol) and chromium trioxide(3.27 mg, 32.8 μmol) in Acetonitrile (3.0 mL) was stirred at roomtemperature for 30 min. Then acetic anhydride (92.5 μL, 984 μmol) wasadded. The reaction mixture was cooled to 0° C. and 2-3 (50 mg, 164μmol) was added in one portion and the reaction mixture was furtherstirred for 30 min at room temperature. After completion of thereaction, ice-water (15-20 mL) was added and the mixture was extractedwith ethyl acetate (3×50 mL). The combined organic layer was washed withsaturated NaHCO₃ solution, saturated Na₂S203 solution, and finally withbrine. The organic phase was dried over anhydrous sodium sulfate and thesolvent was removed under reduced pressure. The crude product wasfiltered through silica gel column using ethyl acetate as eluent toobtain Compound 2 as white solid. Yield-40%; ¹H NMR (400 MHz, DMSO-d6) δ10.86 (s, 1H), 8.34 (d, J=7.96 Hz, 1H), 8.24 (d, J=7.36 Hz, 1H), 8.11(t, J=7.78 Hz, 1H), 5.26 (dd, J=12, 3.08 Hz, 1H), 3.18-3.09 (m, 1H),2.66-2.52 (m, 2H), 2.18-2.12 (m, 1H), 1.99-1.82 (m, 2H); LC MS:ES+318.2.

Example 3: Illustrative Preparation of Spiro-Cyclopropyl Glutarimide

Step 1: A 25 mL 2 neck RB flask was charged with1-(2-((tert-butoxycarbonyl)amino)-2-carboxyethyl)cyclopropanecarboxylicacid (200 mg, 731 μmol) in Xylene (5 mL). Urea (87.6 mg, 1.46 mmol) wasadded to the reaction mixture and was heated at 150° C. for 5 hours. Itwas concentrated under reduced pressure and was purified by silica gel(100-200 mesh) column chromatography by using 1% methanol indichloromethane to provide tert-butyl(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)carbamate (30.0 mg, 117 μmol,16.2%) as off white solid.

Step 2: A 10 mL round bottom flask was charge with tert-butyl(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)carbamate (20 mg, 78.6 μmol) in 4MDioxane-HCl (1 mL) at 00C. It was stirred at RT for 2 h. It wasconcentrated under reduced pressure to provide7-amino-5-azaspiro[2.5]octane-4,6-dione hydrochloride (12.0 mg, 62.9μmol, 80.5%) as a white solid.

A 10 ml round bottom flask was charged with7-amino-5-azaspiro[2.5]octane-4,6-dione hydrochloride (10 mg, 52.4 μmol)in Acetic acid (2 mL), Triethyl amine (7.30 μL, 52.4 μmol) was added tothe reaction mixture. It was stirred at RT for 10 minutes.isobenzofuran-1,3-dione (7.76 mg, 52.4 μmol) was added to the reactionmixture. It was heated at 120° C. for 4 h. It was cooled to RT and wasconcentrated under reduced pressure. It was purified by preparative TLC(3% methanol-dichloromethane) to provide2-(4,6-dioxo-5-azaspiro[2.5]octan-7-yl)isoindoline-1,3-dione (5.00 mg,17.5 μmol, 33.7%) as off white solid. TLC system: 5% MeOH/DCM, Rf:0.2,NMR ¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (s, 1H), 7.92 (m, 4H), 5.16 (dd,J=12, 5.6 Hz, 1H), 3.03 (t, J=12 Hz, 1H), 1.62 (m, 1H), 1.42 (m, 1H),1.05 (m, 2H), 0.85 (m, 1H); LCMS ES-283.1.

TABLE 1 Cmpd # Structure Kd 1

+ 2

+ 3

++ In Table 1 above + is >100 μM and ++ is between 1 μM and 1000 μM

Example 4: CRBN-DDB1 Fluorescence Polarization (FP) Assay

Measuring compound ligand binding to CRBN-DDB1 was carried out using anestablished sensitive and quantitative in vitro fluorescencepolarization (FP) based binding assay. (See, I. J. Enyedy et al, J. Med.Chem., 44: 313-4324 [2001]). Compounds were dispensed from seriallydiluted DMSO stock into black 384-well compatible fluorescencepolarization plates using an Echo acoustic dispenser. Compound bindingto CRBN-DDB1 was measured by displacement of either a(−)-Thalidomide-Alexa Fluor® or Pomalidomide-fluorescein conjugatedprobe dye. A 20 μL mixture containing 400 nM CRBN-DDB1 and 5 nM probedye in 50 mM Hepes, pH 7.4, 200 mM NaCl, 1% DMSO and 0.1% pluronicacid-127 acid was added to wells containing compound and incubated atroom temperature for 60 min. Matching control wells excluding CRBN-DDB1were used to correct for background fluorescence. Plates were read on anEnvision plate reader with appropriate FP filter sets. The corrected S(perpendicular) and P (parallel) values were used to calculatefluorescence polarization (FP) with the following equation:FP=1000*(S-G*P)/(S+G*P). The fractional amount of bound probe (FB) toCRBN-DDB1 as a function of compound concentration was fitted accordingto Wang; FEBS Letters 360, (1995), 111-114 to obtain fits for parameteroffsets and binding constant (KA) of competitor compound.

Example 5: Cell Viability Analysis

RPMI 1640 medium and fetal bovine serum (FBS) were purchased from Gibco(Grand Island, N.Y., USA). CellTiter-Glo® 2.0 Assay was purchased fromPromega (Medison, Wis., USA). MOLT4.1 (WT) cell line was purchased fromATCC (Manassas, Va., USA) and MOLT4.2 (CRBN Knock Out) cell line wasgenerated in house. Cell culture flasks and 384-well microplates wereacquired from VWR (Radnor, Pa., USA).

MOLT4.1 and MOLT4.2 cell viability was determined based onquantification of ATP using CellTiter-Glo® 2.0 luminescent Assay kit,which signals the presence of metabolically-active cells. Briefly,MOLT4.1 and MOLT4.2 cells were seeded into 384-well plates at a celldensity of 750 cells per well, the plates were kept at 37° C. with 5%C₀₂ overnight. On the following day, test compounds were added to thecells from a top concentration of 1 μM with 10 points, half logtitration in duplicates. The cells treated in the absence of the testcompound were the negative control and the cells treated in the absenceof CellTiter-Glo® 2.0 were the positive control. At the same day ofcompound treatment, CellTiter-Glo® 2.0 was added to a plate with cellstreated in the absence of the test compound to establish Cytostaticcontrol value (C_(T0)). Cells treated with the test compound wereincubated for 72 hr. CellTiter-Glo reagent was then added to the cellsand Luminescence was acquired on EnVision™ Multilabel Reader(PerkinElmer, Santa Clara, Calif., USA).

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the invention as defined in the appended claim

We claim:
 1. A compound of Formula:

or a pharmaceutically acceptable salt thereof; wherein: A is CR⁸R⁹, C═O,C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,P(O)alkyl, P(O)OH, or P(O)NH₂; A′ is CR¹R², C═O, C═S, C═CH₂, SO₂, S(O),P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, or P(O)NH₂;A″ is CR³R⁴, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, or P(O)NH₂; X is independentlyselected from NH, NR¹¹, CH₂, CHR¹², C(R¹²)₂, O, and S; Z is O, S, CH₂,CH(C₁-C₄alkyl), or C(C₁-C₄alkyl)₂; n is 0, 1, 2, 3, 4, or 5; m is 1 or3;

is a single or double bond; R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, and R¹³ areindependently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine,—NHalkyl, and —Nalkyl₂; or R¹ and R² form a 3-, 4-, 5-, or 6-memberedspirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising1 or 2 heteroatoms selected from N and O; or R³ and R⁴ form a 3-, 4-,5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-memberedspiroheterocycle comprising 1 or 2 heteroatoms selected from N and O; orR⁶ and R⁷ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-,or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selectedfrom N and O; or R⁸ and R⁹ form a 3-, 4-, 5-, or 6-memberedspirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising1 or 2 heteroatoms selected from N and O; or R¹ and R³ form a 1 or 2carbon bridged ring; or R¹ and R⁷ form a 1 or 2 carbon bridged ring; orR³ and R⁷ form a 1 or 2 carbon bridged ring; or R¹³ and R¹ form a 3, 4,5, or 6 carbon fused ring; or R¹³ and R⁴ form a 1 or 2 carbon bridgedring; or R¹³ and R⁵ form a 3, 4, 5, or 6 carbon fused ring wherein R⁵ ison the carbon alpha to R¹³ or a 1, 2, 3, or 4 carbon bridged ringwherein R⁵ is not on the carbon alpha to R¹³; R⁵ is selected at eachinstance from: alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide,amino, —NHalkyl, —N(alkyl)₂, —NHSO₂alkyl, —N(alkyl)SO₂alkyl, —NHSO₂aryl,—N(alkyl)SO₂aryl, —NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl,—N(alkyl)SO₂alkynyl, and haloalkyl; or two R⁵ substituents together withthe carbon atom(s) to which they are bound can form a 3, 4, 5 or 6membered ring; Q¹, Q², Q³, and Q⁴ are independently selected from CH,CR¹², and N; and wherein no more than two of Q¹, Q², Q³, and Q⁴ are N;R¹¹ is independently selected from alkyl, alkenyl, alkynyl, C(O)H,—C(O)OH, —C(O)alkyl, and —C(O)Oalkyl; and R¹² is independently selectedfrom alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino,—C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —NHalkyl, —N(alkyl)₂,—NHSO₂alkyl, —N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO₂aryl,—NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,cyano, nitro, nitroso, —SH, —Salkyl, and haloalkyl; wherein forcompounds of Formula III and Formula IV at least one of: a, b, c, d, e,f, g, h, i, or j is satisfied: a. R¹ and R² form a 4, 5, or 6 memberedspiroheterocycle or 3, 4, 5, or 6 membered spirocarbocycle; b. R³ and R⁴form a 4, 5, or 6 membered spiroheterocycle or 3, 4, 5, or 6 memberedspirocarbocycle; c. R⁶ and R⁷ form a 4, 5, or 6 memberedspiroheterocycle or 3, 4, 5, or 6 membered spirocarbocycle; d. R⁸ and R⁹form a 4, 5, or 6 membered spiroheterocycle or 3, 4, 5, or 6 memberedspirocarbocycle; e. R¹ and R³ form a 1 or 2 carbon bridged ring; f. R¹and R¹³ form a 3, 4, 5, or 6 membered fused ring; g. R⁴ and R¹³ form a 1or 2 carbon bridged ring; h. A is P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, or P(O)NH₂; i. A′ is SO₂, S(O),P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, or P(O)NH₂;or j. A″ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,P(O)alkyl, P(O)OH, or P(O)NH₂; and wherein for compounds of Formula V atleast one of: k, l, m, n, o, p, q, r, s, t, u, v, or w is satisfied: k.m is 3 and n is not 0; l. R¹ and R² form a spirocycle; m. R³ and R⁴ forma spirocycle; n. R⁶ and R⁷ form a spirocycle; o. R⁸ and R⁹ form aspirocycle; p. R¹ and R³ form a 1 or 2 carbon bridged ring; q. R¹ andR¹³ form a 3, 4, 5, or 6 carbon fused ring; r. R⁴ and R¹³ form a 1 or 2carbon bridged ring; s. R¹³ and R⁵ form a 3, 4, 5, or 6 carbon fusedring; t. R¹³ and R⁵ form a 1 or 2 carbon bridged ring; u. A is SO₂,S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, orP(O)NH₂; v. A′ is SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,P(O)alkyl, P(O)OH, or P(O)NH₂; or w. A″ is SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, or P(O)NH₂.
 2. Thecompound of claim 1, wherein the compound is of Formula:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein the compound is of Formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound is of Formula:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein A is C═O or CH₂.
 6. The compound of claim 1, wherein A′ isC═O, C═S, or C═CH₂.
 7. The compound of claim 1, wherein A″ is C═O, C═S,or C═CH₂.
 8. The compound of claim 1, wherein X is NH, S, or O.
 9. Thecompound of claim 1, wherein Q¹, Q², Q³, and Q⁴ are CH.
 10. The compoundof claim 1, wherein Q¹ is CR¹² and one of Q², Q³, and Q⁴ is N.
 11. Thecompound of claim 10, wherein R¹² is amino.
 12. The compound of claim 1,wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 19.A method for treating a patient with abnormal cellular proliferationcomprising administering an effective amount of a compound of claim 1 ora pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier, to a patient in need thereof. 20.The method of claim 19, wherein the patient is a human.